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Review|Articles in Press, 100197

Nanoparticles as a Therapeutic Delivery System for Skin Cancer Prevention and Treatment

Open AccessPublished:March 15, 2023DOI:https://doi.org/10.1016/j.xjidi.2023.100197

      Abstract

      The use of nanoparticles (NPs) as a therapeutic delivery system has expanded markedly over the past decade, particularly regarding applications targeting the skin. The delivery of NP-based therapeutics to the skin requires special consideration due to its role as both a physical and immunologic barrier, and specific technologies must not only take into consideration the target but also the pathway of delivery. The unique challenge this poses has been met with the development of a wide panel of NP-based technologies meant to precisely address these considerations. In this review article, we describe the application of NP-based technologies for drug-delivery targeting the skin, summarize the types of NPs, and discuss the current landscape of NPs for skin cancer prevention and skin cancer treatment as well as future directions within these applications.

      Introduction

      The use of nanoparticles (NPs) in various clinical applications has expanded vastly over the last decade (
      • Cheng CJ
      • Tietjen GT
      • Saucier-Sawyer JK
      • Saltzman WM
      A holistic approach to targeting disease with polymeric nanoparticles.
      ,
      • Huang P
      • Deng H
      • Zhou Y
      • Chen X
      The roles of polymers in mRNA delivery.
      ,
      • Mitchell MJ
      • Billingsley MM
      • Haley RM
      • Wechsler ME
      • Peppas NA
      • Langer R
      Engineering precision nanoparticles for drug delivery.
      ). The term NPs encompasses a wide variety of particle-based materials and formulations in the 1 to 500 nanometer (nm) diameter range that can improve conventional delivery of therapeutics. NPs have been successfully used for delivery of various active agents including a range hydrophobic and hydrophilic small molecule agents, monoclonal antibodies, nucleic acids, and proteins to help overcome barriers in intracellular delivery and trafficking that were not previously possible through traditional modes of administration (
      • Elsabahy M
      • Wooley KL
      Cytokines as biomarkers of nanoparticle immunotoxicity.
      ). Additionally, NPs have shown the capacity to enhance site-directed drug delivery by improving tissue drug levels and cellular uptake. Encapsulation of therapeutics in NPs may allow for flexible delivery and increases stability and solubility of such actives with protection against hydrolytic or enzymatic degradation. Systemic administration of high doses of drugs is often limited by extravasation of the active into off-target sites leading to higher toxicity and adverse effects (
      • Blanco E
      • Shen H
      • Ferrari M
      Principles of nanoparticle design for overcoming biological barriers to drug delivery.
      ). By creating a depot for the cargoes, NPs also allow for a more low-dose, sustained, localized delivery which may also decrease systemic side effects. This is especially advantageous for agents that show significant therapeutic effects that have previously been halted in preclinical or clinical assessment due to systemic toxicity (
      • Dehelean CA
      • Marcovici I
      • Soica C
      • Mioc M
      • Coricovac D
      • Iurciuc S
      • et al.
      Plant-Derived Anticancer Compounds as New Perspectives in Drug Discovery and Alternative Therapy.
      ). Furthermore, NPs can be engineered to promote transport across cell membranes and by including smart systems that target a specific tissue or vasculature. Such targeted delivery strategies can overcome issues with biodistribution first-pass metabolism and facilitate uptake by specific cell types (
      • Cheng CJ
      • Tietjen GT
      • Saucier-Sawyer JK
      • Saltzman WM
      A holistic approach to targeting disease with polymeric nanoparticles.
      ,
      • Mitchell MJ
      • Billingsley MM
      • Haley RM
      • Wechsler ME
      • Peppas NA
      • Langer R
      Engineering precision nanoparticles for drug delivery.
      ). This smart-engineering system allows for enhanced and targeted delivery to sites that were previously inaccessible to free drugs and molecules due to their interactions.
      NPs by most definitions encompass particle sizes ranging from 1 nm to 100 nm, but sizes up to 500 nm are utilized in research and application (
      • Pérez-Herrero E
      • Fernández-Medarde A
      Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy.
      ). As a platform that interacts with multiple external factors such as fluidic forces and dynamics in addition to interactions with other biomolecules and cells, engineering the size of the NPs is an important consideration for targeted delivery to an intended site (
      • Kim D
      • Shin K
      • Kwon SG
      • Hyeon T
      Synthesis and Biomedical Applications of Multifunctional Nanoparticles.
      ,
      • Mandl HK
      • Quijano E
      • Suh HW
      • Sparago E
      • Oeck S
      • Grun M
      • et al.
      Optimizing biodegradable nanoparticle size for tissue-specific delivery.
      ,
      • Mitchell MJ
      • Billingsley MM
      • Haley RM
      • Wechsler ME
      • Peppas NA
      • Langer R
      Engineering precision nanoparticles for drug delivery.
      ). The size of NPs affects the cellular uptake pathways, i.e. phagocytosis, macropinocytosis, and clathrin- or caveolin-mediated endocytosis (
      • Xu E
      • Saltzman WM
      • Piotrowski-Daspit AS
      Escaping the endosome: assessing cellular trafficking mechanisms of non-viral vehicles.
      ,
      • Zhang S
      • Gao H
      • Bao G
      Physical Principles of Nanoparticle Cellular Endocytosis.
      ). Larger NPs may enter cells due to direct transmembrane penetration though it may harm cells due to the large membrane pore created for entry. The optimal size of the NP depends on the location and intended target tissue, i.e. the circulatory half-life, tumor permeability, and biodistribution depending on the intended site. When administered intravenously, there is size-dependent distribution of NPs to different organs depending on the filtration system within the organ itself; generally, particles linger the longest in the blood, liver, and spleen (
      • Hoshyar N
      • Gray S
      • Han H
      • Bao G
      The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction.
      ).
      Drug delivery with NPs often also allows for increased functionality and esthetics of the drugs (
      • Suh HW
      • Lewis J
      • Fong L
      • Ramseier JY
      • Carlson K
      • Peng ZH
      • et al.
      Biodegradable bioadhesive nanoparticle incorporation of broad-spectrum organic sunscreen agents.
      ). Some NPs have been designed to incorporate a bioadhesive quality to increase interactive forces between the material and the tissue or cellular target material, including skin and mucous membranes, thereby increasing specificity and persistence of the NPs. (
      • Deng Y
      • Ediriwickrema A
      • Yang F
      • Lewis J
      • Girardi M
      • Saltzman WM
      A sunblock based on bioadhesive nanoparticles.
      , Duan Wanglin et al., 2021,
      • Mai Y
      • Ouyang Y
      • Qin Y
      • Jia C
      • McCoubrey LE
      • Basit AW
      • et al.
      Poly(lactic acid)-hyperbranched polyglycerol nanoparticles enhance bioadhesive treatment of esophageal disease and reduce systemic drug exposure.
      ,
      • Mohideen M
      • Quijano E
      • Song E
      • Deng Y
      • Panse G
      • Zhang W
      • et al.
      Degradable bioadhesive nanoparticles for prolonged intravaginal delivery and retention of elvitegravir.
      ). For inorganic molecule delivery, NPs facilitate targeted delivery and can be engineered for increased bioadhesiveness, which presents several advantages over the current available formulations targeted towards the skin (
      • Elsabahy M
      • Wooley KL
      Cytokines as biomarkers of nanoparticle immunotoxicity.
      ,
      • Yu L
      • Luo Z
      • Chen T
      • Ouyang Y
      • Xiao L
      • Liang S
      • et al.
      Bioadhesive Nanoparticles for Local Drug Delivery.
      ) including minimizing accumulation in off-target sites that may lead to adverse effects (
      • Soppimath KS
      • Aminabhavi TM
      • Kulkarni AR
      • Rudzinski WE
      Biodegradable polymeric nanoparticles as drug delivery devices.
      ). Herein, we will focus on the various challenges faced with application of NP-based technologies for drug-delivery targeting the skin, the various types of NPs, the current landscape of NPs for skin cancer prevention and skin cancer treatment, and future directions.

      Nanoparticles in the skin

      The skin as a target for NP drug-delivery requires special consideration in that this tissue forms both a physical and immunological barrier. It is an immunologically rich site with various resident immune populations including epidermal Langerhans’ cells and dermal dendritic cells, skin-resident and skin-homing effector and regulatory T cells, and innate lymphoid cells (
      • Nguyen AV
      • Soulika AM
      The Dynamics of the Skin's Immune System.
      ). The stratum corneum is the immediate barrier against the entry of NPs designed to target the skin; it is constituted by a thick matrix of dehydrated, dead keratinocytes within an ordered lipid layer. Depending on the method of administration and desired level of targeting, i.e. topical application with transdermal delivery or direct injection to the site, NPs can be engineered to perform in synergy with the surrounding environment.
      Transdermal delivery refers to when agents are delivered through the skin for systemic or local effect (
      • Krishnan V
      • Mitragotri S
      Nanoparticles for topical drug delivery: Potential for skin cancer treatment.
      ,
      • Severino P
      • Fangueiro JF
      • Ferreira SV
      • Basso R
      • Chaud MV
      • Santana MHA
      • et al.
      Nanoemulsions and nanoparticles for non-melanoma skin cancer: effects of lipid materials.
      ) (Figure 1). For typical drug formulations, penetrance and delivery into and through the stratum corneum, epidermis, and into the dermis (and thus availability for systemic absorption), can be facilitated by excipient agents including fatty acids, esters, alcohols, amines, and lipids that physiochemically alter the skin barrier (
      • Desai P
      • Patlolla RR
      • Singh M
      Interaction of nanoparticles and cell-penetrating peptides with skin for transdermal drug delivery.
      ,
      • Kanikkannan N
      • Kandimalla K
      • Lamba SS
      • Singh M
      Structure-activity relationship of chemical penetration enhancers in transdermal drug delivery.
      ,
      • Karande P
      • Jain A
      • Ergun K
      • Kispersky V
      • Mitragotri S
      Design principles of chemical penetration enhancers for transdermal drug delivery.
      ). NP-facilitated drug delivery to the skin, however, comes with a myriad of challenges as the skin has evolved to be highly protective against most naturally occurring environmental nanoparticles (e.g. bacteria, dust, viral particles, or allergens) that do not readily penetrate the skin unless the skin barrier is disrupted by disease or specific interventions (
      • Nohynek GJ
      • Lademann J
      • Ribaud C
      • Roberts MS
      Grey goo on the skin? Nanotechnology, cosmetic and sunscreen safety.
      ,
      • Prow TW
      • Grice JE
      • Lin LL
      • Faye R
      • Butler M
      • Becker W
      • et al.
      Nanoparticles and microparticles for skin drug delivery.
      ). Topically applied NPs have been engineered for the specific transdermal and dermal delivery to target damaged skin, e.g. compromised barrier function as seen in inflammatory skin diseases such as atopic dermatitis and psoriasis, genetically altered skin as seen in certain disorders of cornification, or in aging skin. Other topical approaches aim to intrinsically and safely enhance skin permeability through the NP composition, often by disrupting the stratum corneum barrier by creating micropores (
      • Tadros AR
      • Romanyuk A
      • Miller IC
      • Santiago A
      • Noel RK
      • O'Farrell L
      • et al.
      STAR particles for enhanced topical drug and vaccine delivery.
      ). For other topical or local delivery strategies, there may be other engineered NP surfaces or properties to better accommodate the target lesion, including cutaneous malignancy or damaged / wounded skin. For instance, the site of cutaneous tumors is more acidic and has receptors allowing localizable targeting with conjugated antibodies on NPs to target the tumor matrix. NPs engineered with bioadhesive properties can be delivered to a skin (or mucosal) surface, or as a simple subcutaneous or peritumoral or intratumoral injection, to improve skin-delivery strategies (
      • Hu JK
      • Suh HW
      • Qureshi M
      • Lewis JM
      • Yaqoob S
      • Moscato ZM
      • et al.
      Nonsurgical treatment of skin cancer with local delivery of bioadhesive nanoparticles.
      ).
      Figure thumbnail gr1
      Figure 1Topical and Intracutaneous Delivery of Nanoparticles
      Depending on the agent and lesion or target of concern, the topical delivery of free agents in traditional vehicles may not achieve adequate penetration into deeper lesions or may require high concentrations and repetitive application, and NPs may offer advantages to address these challenges. For example, topical chemotherapy with 5-fluorouracil or an immunomodulator such as imiquimod can lead to local side effects such as skin irritancy and even ulceration, as well as the risk of systemic absorption and toxicity that is increased by the necessary repetitive application (
      • Prausnitz MR
      • Langer R
      Transdermal drug delivery.
      ,
      • Tadros AR
      • Romanyuk A
      • Miller IC
      • Santiago A
      • Noel RK
      • O'Farrell L
      • et al.
      STAR particles for enhanced topical drug and vaccine delivery.
      ).
      Despite the many design strategies, efficient and effective topical delivery of NPs in a clinical setting remains challenging. There is some evidence that there is skin penetration into the stratum spinosum then to the dermis for particles that are smaller than 10 nm; however, there is little evidence of penetration with larger molecular sizes (
      • Prow TW
      • Grice JE
      • Lin LL
      • Faye R
      • Butler M
      • Becker W
      • et al.
      Nanoparticles and microparticles for skin drug delivery.
      ,
      • Ryman-Rasmussen JP
      • Riviere JE
      • Monteiro-Riviere NA
      Variables Influencing Interactions of Untargeted Quantum Dot Nanoparticles with Skin Cells and Identification of Biochemical Modulators.
      ). For particle sizes greater than 20 nm, the NPs may depot within pores and hair follicles and penetrate into the peri-follicular dermis, albeit usually without a more diffuse penetration into the dermis.

      Types of nanoparticles

      Lipid-Based NPs

      Lipid-based NPs usually include spherical platforms with a lipid layer (Figure 2). These lipid NPs can be binned largely into two types of NPs: liposomes, and solid lipid NP (SLN) or lipid NP (LNP); liposomes contain at least one lipid bilayer while LNPs are a spherical nanoparticle composed of an outer lipid layer that may not necessarily include a continuous lipid bilayer. For delivery and application to the skin, lipid-based NPs can be a favorable material as lipids are a key component of the stratum corneum layer and are fundamental in maintaining skin integrity and maintaining moisture. Liposomes and lipid NPs are essentially similar in that they both are formed with micellar structures. However, liposomes are traditionally formed by phospholipid bilayer or materials that mimic the biological membranes while LNPs may or may not have a lipid or engineered lipid contiguous bilayer with the active, ranging from drugs to peptides, in the particle core. The lipid-based NPs can be versatile in their composition because they can deliver hydrophobic, hydrophilic, and lipophilic molecules depending on the location of the entrapment of the molecule. Differential small molecule encapsulation within the same NP allows, for example, a conjugated outer shell to target a specific environment or tumor matrix with an inner core of therapeutic release upon contact with the surface.
      Figure thumbnail gr2
      Figure 2Types of Nanoparticles and their Advantages and Disadvantages
      Liposomes, however, can have increased uptake through macro and micropinocytosis and endosomal uptake and faster clearance, due to their similarity in structure with physiological liposomes and vesicles (
      • Sercombe L
      • Veerati T
      • Moheimani F
      • Wu SY
      • Sood AK
      • Hua S
      Advances and Challenges of Liposome Assisted Drug Delivery.
      ). There is also often rapid leakage of water-soluble drugs from the liposomal cores in the presence of blood components. Therefore, liposomes are also often created with surface modifications that include polymers, peptides, or other compatible material to extend their circulations (
      • Sercombe L
      • Veerati T
      • Moheimani F
      • Wu SY
      • Sood AK
      • Hua S
      Advances and Challenges of Liposome Assisted Drug Delivery.
      ).
      LNPs typically contain cationic lipids, ionizable lipids, or other lipids within the outer shell that help encapsulate the drug or molecule of choice in their aqueous core. These other lipids are incorporated to improve stability and compatibility in the compartment, to enhance delivery to a specific site, and to enhance escape from endosomes. The cationic and ionizable lipids allow for easy complex formation with a charged material, such as a nucleic acid, and allows for endosomal escape. Additional components of LNPs include other supportive lipids, e.g. cholesterol and phosphatidylcholine, that facilitate membrane fusion. Incorporation of lipids modified with polyethylene glycol (PEG) may be used to mitigate opsonization and reticuloendothelial clearance (
      • Cheng X
      • Lee RJ
      The role of helper lipids in lipid nanoparticles (LNPs) designed for oligonucleotide delivery.
      ). PEGylation is also a method used to increase serum half-life of the conjugate after systemic administration and increase the therapeutic potential of the NP (
      • Mishra P
      • Nayak B
      • Dey RK
      PEGylation in anti-cancer therapy: An overview.
      ). A derivative of SLNs are nanostructured lipid carriers (NLCs), which are formed by both solid and liquid phase lipids and exhibit improved loading capacity and stability relative to SLNs.

      Polymer-based NPs

      Various polymers have been used in NP formulation with the intent to control size and properties of the NP, minimize the loss of drug and premature degradation of the NPs, and produce materials that are easily manufactured and stored. Polymeric outer-shell can help protect the NPs from protein absorption including the clearance by opsonins, thereby prolonging blood circulation or target site persistence (
      • Zhang C
      • Li Q
      • Wu C
      • Wang J
      • Su M
      • Deng J
      Hypoxia-responsive nanogel as IL-12 carrier for anti-cancer therapy.
      ). Despite their solid forms, polymers used in biomedical applications are biodegradable; most common polymers degrade by hydrolysis enzymatic cleavage in biological fluids, such that larger molecular weight polymers become lower in molecular weight over time, thus allowing for controlled release of the therapeutic from the system and ultimately leading to complete disappearance of the polymer (
      • Gunatillake PA
      • Adhikari R
      Biodegradable synthetic polymers for tissue engineering.
      ). Polymeric NPs utilize polymer chains as the main NP agents, but as described above, polymers have also been commonly used as a modifying agent on drugs or on lipid NPs. The most commonly used surface polymers include polyglycerols, polycyanoacrylate (PCA), and polyethylene glycol (PEG) (
      • Soppimath KS
      • Aminabhavi TM
      • Kulkarni AR
      • Rudzinski WE
      Biodegradable polymeric nanoparticles as drug delivery devices.
      ). Micellar formation is also often employed by using block copolymers—such as a block co-polymer of polylactide-co-glycolide (PLGA) and PEG—which allows for the formation of NPs with differing inner core (PLGA) and surface (PEG) properties. This incorporates an amphiphilic polymer, formed by conjugation of different polymers for formation of the micelle. Commonly used hydrophobic polymers include polylactic acid (PLA), polycaprolactone (PCL), and PLGA (
      • Guo X
      • Wang L
      • Wei X
      • Zhou S
      Polymer-based drug delivery systems for cancer treatment.
      ).
      Polymer NPs can encapsulate therapeutics of various hydrophobicity as the agents can be encapsulated in the core—which might be a multiphase matrix—or conjugated/adsorbed to the surface of the NP. The NP shape and therapeutic dispersion depends on the method of preparation (
      • Soppimath KS
      • Aminabhavi TM
      • Kulkarni AR
      • Rudzinski WE
      Biodegradable polymeric nanoparticles as drug delivery devices.
      ). Nanospheres are characterized by uniform dispersion of the therapeutic agent throughout the NP matrix, whereas the nanocapsules have the therapeutic encapsulated within a hollow core. The kinetics of drug release from polymer NPs depends on the drug, diffusion within the core matrix, pH and other features of the biological environment, and other erosion/diffusion processes (
      • Soppimath KS
      • Aminabhavi TM
      • Kulkarni AR
      • Rudzinski WE
      Biodegradable polymeric nanoparticles as drug delivery devices.
      ). The in vitro release rate of the therapeutic from polymer NPs is often studied to demonstrate a controlled and steady release, although the rate of release measured in vitro does not always predict the rate of release in the biological environment.
      Polymer NPs, due to their engineerability with various surface and core modifications, have been used to carry drugs, nucleic acids, and other small molecules. Delivery of a variety of nucleic acid therapeutics have been demonstrated including siRNA (
      • Woodrow KA
      • Cu Y
      • Booth CJ
      • Saucier-Sawyer JK
      • Wood MJ
      • Saltzman WM
      Intravaginal gene silencing using biodegradable polymer nanoparticles densely loaded with small-interfering RNA.
      ), mRNA (

      Suberi A, Grun MK, Mao T, Israelow B, Reschke M, Grundler J, et al. Inhalable polymer nanoparticles for versatile mRNA delivery and mucosal vaccination. bioRxiv 2022.

      ), and CRISPR Cas-9 gene editing machinery (Duan Li et al., 2021). When loading these compounds in the core, charged polymers such as polyethylenimine (PEI) (
      • Helmschrodt C
      • Hobel S
      • Schoniger S
      • Bauer A
      • Bonicelli J
      • Gringmuth M
      • et al.
      Polyethylenimine Nanoparticle-Mediated siRNA Delivery to Reduce alpha-Synuclein Expression in a Model of Parkinson's Disease.
      ), polyamidoamine (PAMAM) (
      • Dabkowska M
      • Luczkowska K
      • Roginska D
      • Sobus A
      • Wasilewska M
      • Ulanczyk Z
      • et al.
      Novel design of (PEG-ylated)PAMAM-based nanoparticles for sustained delivery of BDNF to neurotoxin-injured differentiated neuroblastoma cells.
      ), poly(beta amino esters) (
      • Patel AK
      • Kaczmarek JC
      • Bose S
      • Kauffman KJ
      • Mir F
      • Heartlein MW
      • et al.
      Inhaled Nanoformulated mRNA Polyplexes for Protein Production in Lung Epithelium.
      ), or poly(amine-co-esters) (
      • Grun MK
      • Suberi A
      • Shin K
      • Lee T
      • Gomerdinger V
      • Moscato ZM
      • et al.
      PEGylation of poly(amine-co-ester) polyplexes for tunable gene delivery.
      ) are frequently used . Due to their cationic nature, these polymers have also shown to have some cytotoxicity to the surrounding cells when the vehicle delivery in vivo is observed with TUNEL stain (
      • Godbey WT
      • Wu KK
      • Mikos AG
      Poly(ethylenimine)-mediated gene delivery affects endothelial cell function and viability.
      ). This toxicity appears to be related to the excess cationic charge on the NP surface, and can be dramatically reduced by using cationic polymers with reduced charge density (
      • Fields RJ
      • Quijano E
      • McNeer NA
      • Caputo C
      • Bahal R
      • Anandalingam K
      • et al.
      Modified poly(lactic-co-glycolic acid) nanoparticles for enhanced cellular uptake and gene editing in the lung.
      ) or shielding charge with surface polymers such as PEG (
      • Grun MK
      • Suberi A
      • Shin K
      • Lee T
      • Gomerdinger V
      • Moscato ZM
      • et al.
      PEGylation of poly(amine-co-ester) polyplexes for tunable gene delivery.
      ).
      Many of these polymers have been extensively studied, including in clinical trials. Notable examples are PEG and PLA: there are already several FDA-approved therapeutics and clinical trials employing PEG conjugated delivery of chemotherapy or immunomodulator such as recombinant human granulocyte colony-stimulating factor for solid tumors (
      • Huang W
      • Liu J
      • Zeng Y
      • Wu F
      • Li N
      • Chen K
      • et al.
      Randomized controlled clinical trial of polyethylene glycol recombinant human granulocyte colony-stimulating factor in the treatment of neutropenia after chemotherapy for breast cancer.
      ,
      • Qin Y
      • Han X
      • Wang L
      • Du P
      • Yao J
      • Wu D
      • et al.
      A phase I study of different doses and frequencies of pegylated recombinant human granulocyte-colony stimulating factor (PEG rhG-CSF) in patients with standard-dose chemotherapy-induced neutropenia.
      ,
      • Xiao RZ
      • Zeng ZW
      • Zhou GL
      • Wang JJ
      • Li FZ
      • Wang AM
      Recent advances in PEG-PLA block copolymer nanoparticles.
      ) For instance, PEGylation of cytokines such as GM-CSF and interferons has demonstrated significant increase in biological half-life in plasma (
      • Bonanno G
      • Procoli A
      • Mariotti A
      • Corallo M
      • Perillo A
      • Danese S
      • et al.
      Effects of pegylated G-CSF on immune cell number and function in patients with gynecological malignancies.
      ,
      • Calabresi PA
      • Kieseier BC
      • Arnold DL
      • Balcer LJ
      • Boyko A
      • Pelletier J
      • et al.
      Pegylated interferon beta-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study.
      ,
      • Molineux G
      The design and development of pegfilgrastim (PEG-rmetHuG-CSF, Neulasta).
      ,
      • Thomas T
      • Foster G
      Nanomedicines in the treatment of chronic hepatitis C--focus on pegylated interferon alpha-2a.
      ,
      • Yuan W
      • Huang D
      • Wu D
      • Chen Y
      • Ma K
      • Han M
      • et al.
      Pegylated Interferon-a (IFN-a) Enhances the Inhibitory Effect of Natural Killer Cells on Regulatory T Cells via IFN-gamma in Chronic Hepatitis B.
      ).

      Metal and metal-oxide based NPs

      Gold, silver, and copper are the most commonly used metals for the synthesis of metal-based NPs which have been used in a variety of applications from biological labeling to therapeutic delivery (
      • Bobo D
      • Robinson KJ
      • Islam J
      • Thurecht KJ
      • Corrie SR
      Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date.
      ). In dermatologic and skin based applications, metal-based particles, such as silver NPs, have been used for their effective antibacterial and antifungal properties (
      • Niska K
      • Zielinska E
      • Radomski MW
      • Inkielewicz-Stepniak I
      Metal nanoparticles in dermatology and cosmetology: Interactions with human skin cells.
      ). Metal-based NP effectiveness and toxicity are intrinsically related to size, shape, and zeta potential. For example, several studies have indicated an increase in antibacterial properties of the NP with decreasing diameter, with particles around 10 nm demonstrating the greatest antimicrobial effect (
      • Agnihotri S
      • Mukherji S
      • Mukherji S
      Size-controlled silver nanoparticles synthesized over the range 5–100 nm using the same protocol and their antibacterial efficacy.
      ,
      • Ivask A
      • Kurvet I
      • Kasemets K
      • Blinova I
      • Aruoja V
      • Suppi S
      • et al.
      Size-dependent toxicity of silver nanoparticles to bacteria, yeast, algae, crustaceans and mammalian cells in vitro.
      ). Zeta potential can influence the biocompatibility with the environment, and the change in the environment’s pH or ionic strength can also affect nanoparticle stability in the medium (
      • Sizochenko N
      • Mikolajczyk A
      • Syzochenko M
      • Puzyn T
      • Leszczynski J
      Zeta potentials (zeta) of metal oxide nanoparticles: A meta-analysis of experimental data and a predictive neural networks modeling.
      ). NP with positive zeta potential have been demonstrated to be associated with increased hemolytic potential, inflammation, and recruitment of granulocytes in lung (
      • Cho WS
      • Duffin R
      • Thielbeer F
      • Bradley M
      • Megson IL
      • Macnee W
      • et al.
      Zeta potential and solubility to toxic ions as mechanisms of lung inflammation caused by metal/metal oxide nanoparticles.
      ). Because these are inorganic engineerable materials, they can be more precisely engineered to have specific sizes and structures.
      Gold-based NPs are well studied and have a wide range of applications including delivery of chemotherapy, peptide-based, and photosensitizing agents for photothermal therapy. Photothermal therapy is a method of cancer treatment that incorporates a photothermal agent (PTA) in the NP to be released to tumors and induce cancer cell death through energy conversion. This leverages the phenomenon of surface plasmon resonance, where resonant conditions are achieved between the oscillations of valence electrons with the frequency of incident light. Through this resonance, there is an enhanced conversion of light energy to thermal energy as absorption to emission is large enough to generate heat. By localizing gold NPs with PTA, there can be targeted light therapy that induces cancer cell destruction with conversion of the light energy into heat. However, gold has been shown to cause acute and chronic changes in gene expression, hypothesized to be due to their affinity for DNA (
      • Qiu TA
      • Bozich JS
      • Lohse SE
      • Vartanian AM
      • Jacob LM
      • Meyer BM
      • et al.
      Gene expression as an indicator of the molecular response and toxicity in the bacterium Shewanella oneidensis and the water flea Daphnia magna exposed to functionalized gold nanoparticles.
      ). Silver NPs have similarly been used for purposes of photodynamic or photothermal therapy. In antitumor applications, silver particles offer the potential to provide dual anti-tumoricidal effect with an encapsulated chemotherapeutic drug followed by irradiation of the administered site to induce cell death.
      Metal oxide NPs such as zinc oxide (ZnO) and titanium oxide (TiO2) have been used as actives in sunscreen formulations owing to their capacity to both reflect and absorb ultraviolet radiation (UVR) (
      • Cole C
      • Shyr T
      • Ou-Yang H
      Metal oxide sunscreens protect skin by absorption, not by reflection or scattering.
      ). Although largely considered incapable of penetrating the stratum corneum, reduction of particle size via micronization or nanonization both improves performance and raises some concerns about whether size reduction might increase penetrance. There is also some evidence that both metal and metal-oxide NPs may exert toxic effects through generation of reactive oxygen species (ROS), which may accelerate aging of the skin and photocarcinogenicity (
      • Tran DT
      • Salmon R
      Potential photocarcinogenic effects of nanoparticle sunscreens.
      ), as has been demonstrated for some organic compound sunscreen agents. When ZnO and TiO2 structures are excited with UVR, electron excitation leads to formation of radicals with surface bound molecules (
      • Fu PP
      • Xia Q
      • Hwang H-M
      • Ray PC
      • Yu H
      Mechanisms of nanotoxicity: generation of reactive oxygen species.
      ).
      Due to increasing concerns of toxicity of metal based NPs and their potential accumulation in sensitive organs, current research trends have started to shift from systemic and local injections of metal-based NPs (
      • Sengul AB
      • Asmatulu E
      Toxicity of metal and metal oxide nanoparticles: a review.
      ). In topical applications, several studies have found that penetration is below the level of detection and that compared to macro-sized particles, nano-sized ZnO and TiO2 do not exhibit an increased penetration potential (
      • Cross SE
      • Innes B
      • Roberts MS
      • Tsuzuki T
      • Robertson TA
      • McCormick P
      Human skin penetration of sunscreen nanoparticles: in-vitro assessment of a novel micronized zinc oxide formulation.
      ,
      • Ilves M
      • Palomäki J
      • Vippola M
      • Lehto M
      • Savolainen K
      • Savinko T
      • et al.
      Topically applied ZnO nanoparticles suppress allergen induced skin inflammation but induce vigorous IgE production in the atopic dermatitis mouse model.
      ,
      • Kiss B
      • Bíró T
      • Czifra G
      • Tóth BI
      • Kertész Z
      • Szikszai Z
      • et al.
      Investigation of micronized titanium dioxide penetration in human skin xenografts and its effect on cellular functions of human skin-derived cells.
      ,
      • Leite-Silva VR
      • Le Lamer M
      • Sanchez WY
      • Liu DC
      • Sanchez WH
      • Morrow I
      • et al.
      The effect of formulation on the penetration of coated and uncoated zinc oxide nanoparticles into the viable epidermis of human skin in vivo.
      ,
      • Wang SQ
      • Balagula Y
      • Osterwalder U
      Photoprotection: a Review of the Current and Future Technologies.
      ). However, concerns regarding the effects of inhalation in spray products have been raised given their potential to deposit along the airway down to the alveoli. Studies demonstrating the safety of nano-metal particles have yielded variable results, but they have consistently demonstrated that inhaled nanoparticles can be found in the lungs depending on the metal particulate type and that they can diffuse and translocate to other parts of the body (
      • Bermudez E
      • Mangum JB
      • Wong BA
      • Asgharian B
      • Hext PM
      • Warheit DB
      • et al.
      Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles.
      ,
      • Dreno B
      • Alexis A
      • Chuberre B
      • Marinovich M
      Safety of titanium dioxide nanoparticles in cosmetics.
      ,
      • Oyabu T
      • Myojo T
      • Lee BW
      • Okada T
      • Izumi H
      • Yoshiura Y
      • et al.
      Biopersistence of NiO and TiO(2) Nanoparticles Following Intratracheal Instillation and Inhalation.
      ,
      • Zhang S
      • Gao H
      • Bao G
      Physical Principles of Nanoparticle Cellular Endocytosis.
      ).
      Membrane/ Vesicle/ Polysaccharide
      Some NPs are derived from natural polymers such as membranes of plants, viruses, or yeast, and polysaccharide-derived materials such as lecithin, dextran, alginate, or chitosan. These NPs were created to take advantage of the natural properties of the plant polymers, and improve transport of the compounds in blood. Virus-like particles (VLP) are defined as protein structures isolated from viruses lacking the infectious and genetic component to the mammalian host. These have been used in the context of cancer vaccines as the particles themselves can also serve as an adjuvant to enhance immunization. Viruses activate the host immune system due to the presence of pathogen associated molecular patterns that can be recognized by pattern-recognition receptors on various cells of the immune system, including resident dendritic cells, to activate a cascade of immune reaction and trigger immediate innate immune responses that are delayed and antigen-specific. VLPs share this molecular structure without the toxicity and therefore can enhance immunogenicity when delivered to the host (
      • Neek M
      • Kim TI
      • Wang S-W
      Protein-based nanoparticles in cancer vaccine development.
      ).
      Chitosan is an example of a natural polysaccharide. It is a cationic, linear polysaccharide that is made up of randomly distributed and forms of glucosamines and N-acetylglucosamines (
      • Yu L
      • Luo Z
      • Chen T
      • Ouyang Y
      • Xiao L
      • Liang S
      • et al.
      Bioadhesive Nanoparticles for Local Drug Delivery.
      ). It is notably bioadhesive, mucoadhesive, and biodegradable and has been applied in several types of therapeutics for treatment of skin diseases due to these properties. There is also evidence that chitosan supports skin reconstruction and wound healing (
      • Cordenonsi LM
      • Faccendini A
      • Catanzaro M
      • Bonferoni MC
      • Rossi S
      • Malavasi L
      • et al.
      The role of chitosan as coating material for nanostructured lipid carriers for skin delivery of fucoxanthin.
      ,
      • Jayakumar R
      • Menon D
      • Manzoor K
      • Nair SV
      • Tamura H
      Biomedical applications of chitin and chitosan based nanomaterials—A short review.
      ,
      • Sandri G
      • Bonferoni MC
      • Rossi S
      • Ferrari F
      • Mori M
      • Del Fante C
      • et al.
      Platelet lysate formulations based on mucoadhesive polymers for the treatment of corneal lesions.
      ). Chitosan interacts with skin lipids due to charge and hydrogen bonding with its amino and carboxyl groups, improving its potential as a topical drug carrier for improved diffusion through the skin layers (
      • Nawaz A
      • Wong TW
      Chitosan-Carboxymethyl-5-Fluorouracil-Folate Conjugate Particles: Microwave Modulated Uptake by Skin and Melanoma Cells.
      ). With its positive charge, chitosan can be also conjugated with polyanions to form NPs with engineered properties (
      • Li S
      • Zhang F
      • Yu Y
      • Zhang Q
      A dermatan sulfate-functionalized biomimetic nanocarrier for melanoma targeted chemotherapy.
      ). These naturally derived NPs do not have the high purity and reproducibility associated with synthetic LNPs, polymer NPs, and metal-based NPs. For more synthetically derived NPs, conjugation with these proteins or vesicles have been done to improve cellular uptake (
      • Zhan X
      • Teng W
      • Sun K
      • He J
      • Yang J
      • Tian J
      • et al.
      CD47-mediated DTIC-loaded chitosan oligosaccharide-grafted nGO for synergistic chemo-photothermal therapy against malignant melanoma.
      ).

      NPs in skin cancer prevention

      Skin cancer remains the most commonly diagnosed cancer in the United States, resulting in an estimated cost of $8.1 billion dollars per year (
      • Guy Jr., GP
      • Machlin SR
      • Ekwueme DU
      • Yabroff KR
      Prevalence and costs of skin cancer treatment in the U.S., 2002-2006 and 2007-2011.
      ). UVR is the major environmental factor for skin cancer development, with an estimated contribution to 65% of melanoma and 90% of non-melanoma skin cancer cases, suggesting that the majority of cases are preventable by limiting the skin’s exposure to UVR (
      • D’Orazio J
      • Jarrett S
      • Amaro-Ortiz A
      • Scott T
      UV Radiation and the Skin.
      ). In addition to wearing sun-protective clothing and avoiding sun exposure during the day’s peak exposure times, sunscreens can be an effective tool to protect against the development of skin cancer, as well as acute sunburn and effects of photoaging.(
      • Lautenschlager S
      • Wulf HC
      • Pittelkow MR
      ,
      • Nash JF
      Human safety and efficacy of ultraviolet filters and sunscreen products.
      ) There are two main categories of sunscreen agents: organic (e.g. chemical) and inorganic (physical). Organic sunscreens work by absorbing UVR with subsequent dissipation of the energy. Inorganic sunscreens function primarily by reflecting and scattering UVR as well as via absorbance.(
      • Lautenschlager S
      • Wulf HC
      • Pittelkow MR
      ) While inorganic sunscreens protect against both UVA (320-400 nm) and UVB (290-320 nm), organic sunscreens typically have a more narrow window of protection covering primarily either UVA or UVB. Thus, two or more organic chemical sunscreen agents are often combined to achieve broad spectrum coverage.
      Ideal performance criteria for a sunscreen product include retention on the skin surface and photostability, and most of the NPs described in this section revolve around studies demonstrating transdermal or topical delivery of the NPs. Organic sunscreens have been observed in human studies to permeate the skin barrier and enter the systemic circulation, with detection in urine, plasma, and human milk (
      • Hayden CG
      • Roberts MS
      • Benson HA
      Systemic absorption of sunscreen after topical application.
      ,
      • Janjua NR
      • Kongshoj B
      • Andersson AM
      • Wulf HC
      Sunscreens in human plasma and urine after repeated whole-body topical application.
      ,
      • Matta MK
      • Florian J
      • Zusterzeel R
      • Pilli NR
      • Patel V
      • Volpe DA
      • et al.
      Effect of Sunscreen Application on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial.
      ,
      • Matta MK
      • Zusterzeel R
      • Pilli NR
      • Patel V
      • Volpe DA
      • Florian J
      • et al.
      Effect of Sunscreen Application Under Maximal Use Conditions on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial.
      ,
      • Nash JF
      Human safety and efficacy of ultraviolet filters and sunscreen products.
      ,
      • Schlumpf M
      • Kypke K
      • Wittassek M
      • Angerer J
      • Mascher H
      • Mascher D
      • et al.
      Exposure patterns of UV filters, fragrances, parabens, phthalates, organochlor pesticides, PBDEs, and PCBs in human milk: correlation of UV filters with use of cosmetics.
      ). This presents a concern, which is amplified by the potential of sunscreens to interact with endocrine receptors and generate downstream estrogenic, anti-androgenic, and anti-thyroid effects (
      • Heneweer M
      • Muusse M
      • van den Berg M
      • Sanderson JT
      Additive estrogenic effects of mixtures of frequently used UV filters on pS2-gene transcription in MCF-7 cells.
      ,
      • Lorigo M
      • Mariana M
      • Cairrao E
      Photoprotection of ultraviolet-B filters: Updated review of endocrine disrupting properties.
      ). NPs offer a promising opportunity to enhance the desirable effects and minimize the potential concerns of organic sunscreen agents. Table 1 includes examples from the current literature of various sunscreens encapsulated in NPs. Encapsulation of sunscreens within LNPs (Table 1a) can help decrease their rate of release and ability to penetrate human skin (
      • Puglia C
      • Damiani E
      • Offerta A
      • Rizza L
      • Tirendi GG
      • Tarico MS
      • et al.
      Evaluation of nanostructured lipid carriers (NLC) and nanoemulsions as carriers for UV-filters: characterization, in vitro penetration and photostability studies.
      ,
      • Wissing SA
      • Müller RH
      Solid lipid nanoparticles as carrier for sunscreens: in vitro release and in vivo skin penetration.
      ). SLNs were additionally demonstrated to have better photoprotection abilities relative to their unencapsulated forms as well as improved retention in the stratum corneum layer (
      • Gulbake A
      • Jain A
      • Khare P
      • Jain SK
      Solid lipid nanoparticles bearing oxybenzone: in-vitro and in-vivo evaluation.
      ).
      Table 1Applications of Nanoparticles for Skin Cancer Prevention. Table 1b - Metal-based Nanoparticles for Skin Cancer Prevention. Table 1c – Polymeric Nanoparticles for Skin Cancer PreventionTable 1a – Lipid nanoparticles for Skin Cancer Prevention. Table 1b - Metal-based Nanoparticles for Skin Cancer Prevention. Table 1c – Polymeric Nanoparticles for Skin Cancer Prevention
      ApplicationCarrierDrugType of NPRemarksAuthor & year
      Prevention and TreatmentLiposome5-fluorouracil

      Ethylhexyl salicylate

      Squalane
      Nanostructured lipid carriersAim to overcome chemo side effects like photosensitivity – incorporating both chemotherapeutic, chemoprotective and sunscreen agents.

      Nanocarrier free radical scavenging activity at 70%, good release profile, better SPF.
      (
      • Badea G
      • Lacatusu I
      • Ott C
      • Badea N
      • Grafu I
      • Meghea A
      Integrative approach in prevention and therapy of basal cellular carcinoma by association of three actives loaded into lipid nanocarriers.
      )
      PreventionLiposomediindolylmethane derivativeUltra-flexible nanocarriers (deformable vesicles)Developed ultra-flexible nanocarriers for protection against UVR-induced mutagenesis and carcinogenesis.

      Highly permeable across stratum corneum and effectively reduced UVR-induced mutagenesis and incidence of skin tumors.
      (
      • Boakye CHA
      • Patel K
      • Doddapaneni R
      • Bagde A
      • Behl G
      • Chowdhury N
      • et al.
      Ultra-flexible nanocarriers for enhanced topical delivery of a highly lipophilic antioxidative molecule for skin cancer chemoprevention.
      )
      PreventionLiposomeP0

      P2
      Solid lipid nanoparticle, nanostructured lipid carrierNLCs demonstrated ability for controlled release and protective effects against UVB-mediated degradation of P0 and P2.(
      • Daré RG
      • Costa A
      • Nakamura CV
      • Truiti MCT
      • Ximenes VF
      • Lautenschlager SOS
      • et al.
      Evaluation of lipid nanoparticles for topical delivery of protocatechuic acid and ethyl protocatechuate as a new photoprotection strategy.
      )
      PreventionLiposomeQuercetinNanostructured lipid carriersUse of NLCs with quercetin in the developed photoprotective formulation significantly increased in vivo SPF without changing the amount of UV filters.

      Exhibited improved effect on skin barrier hydration.
      (
      • Felippim EC
      • Marcato PD
      • Maia Campos PMBG
      Development of Photoprotective Formulations Containing Nanostructured Lipid Carriers: Sun Protection Factor, Physical-Mechanical and Sensorial Properties.
      )
      Preventionsolid lipid particlesGlyceryl monostearate

      Silanized tio2 caffeine
      Solid lipid particlesCaffeine-loaded solid lipid particles exhibited two-step dissolution profile with initial burst of 60% wt of loaded active.

      Null toxicity.
      (
      • Garcia-Gonzalez CA
      • Sampaio da Sousa AR
      • Argemi A
      • Lopez Periago A
      • Saurina J
      • Duarte CM
      • et al.
      Production of hybrid lipid-based particles loaded with inorganic nanoparticles and active compounds for prolonged topical release.
      )
      PreventionLiposomeOxybenzoneSolid lipid nanoparticlesCream base bearing SLNs exhibited good skin retention and enhanced sun protection compared to cream base only.

      Contact and photocontact allergic dermatitis counteracted with incorporation in lipid matrices.
      (
      • Gulbake A
      • Jain A
      • Khare P
      • Jain SK
      Solid lipid nanoparticles bearing oxybenzone: in-vitro and in-vivo evaluation.
      )
      PreventionLiposomeAvobenzone octyl methoxycinnamate

      TiO2
      Carrier system using carnauba wax + decyl oleateSLN can exhibit synergistic effect to improve SPF.(
      • Nesseem D
      Formulation of sunscreens with enhancement sun protection factor response based on solid lipid nanoparticles.
      )
      PreventionLiposomeSilymarin (anti-oxidant)Solid lipid nanoparticlesSLNs with silymarin demonstrated photoprotection and photostability.(
      • Netto Mpharm G
      • Jose J
      Development, characterization, and evaluation of sunscreen cream containing solid lipid nanoparticles of silymarin.
      )
      PreventionLiposomeAvobenzone

      Octocrylene
      Lipid nanocarriers - melt emulsification coupled with high shear homogenizationLipid nanocarriers co-encapsulated avobenzone and octocrylene and were found to be photostable

      Favorable release profile
      (
      • Niculae G
      • Badea N
      • Meghea A
      • Oprea O
      • Lacatusu I
      Coencapsulation of butyl-methoxydibenzoylmethane and octocrylene into lipid nanocarriers: UV performance, photostability and in vitro release.
      )
      PreventionLiposomeAvobenzoneSolid lipid nanoparticles and nanostructured lipid carriersLipid nanoparticles with avobenzone demonstrated >96% UVA absorption

      Enhanced erythemal UVA protection factor
      (
      • Niculae G
      • Lacatusu I
      • Badea N
      • Meghea A
      Lipid nanoparticles based on butyl-methoxydibenzoylmethane: in vitro UVA blocking effect.
      )
      PreventionLipidAvobenzone

      Octocrylene
      Lipid nanocarriersLipid nanocarriers with renewable vegetable resources (rice brain oil, raspberry seed oil with self-antioxidant properties)

      Exhibited improved photoprotection, antioxidant effects, co-release effectiveness

      Ability to achieve low amount of synthetic UV filters
      (
      • Niculae G
      • Lacatusu I
      • Badea N
      • Stan R
      • Vasile BS
      • Meghea A
      Rice bran and raspberry seed oil-based nanocarriers with self-antioxidative properties as safe photoprotective formulations.
      )
      PreventionLiposomeethylhexyl triazone

      bis-ethylhexyloxyphenol methoxyphenyl triazine

      ethylhexyl methoxycinnamate
      Nanostructured lipid carriersDemonstrated that synergistic effect of NLC and incorporated sunscreens depends not only solid state of lipid but also type of lipid.

      Carnauba wax performed better than reference nanoemulsion and bees wax NLC, increasing SPF value by more than 45% at the same concentration of organic UV filters.
      (
      • Nikolic S
      • Keck CM
      • Anselmi C
      • Muller RH
      Skin photoprotection improvement: synergistic interaction between lipid nanoparticles and organic UV filters.
      )
      PreventionLiposomeoctyl methoxycinnamate

      Tio2
      Oil-in water nanoemulsionsOil-in-water dispersions with octyl methoxycinnamate and TiO2 demonstrated stability and photoprotective properties.(
      • Silva FF
      • Ricci-Junior E
      • Mansur CR
      Nanoemulsions containing octyl methoxycinnamate and solid particles of TiO(2): preparation, characterization and in vitro evaluation of the solar protection factor.
      )
      ApplicationCarrierDrugType of NPRemarksAuthor & year
      PreventionMetal (silver)Silver promoted Znsilver promoted Zn-based nanocompoundsZn(O):Ag increase cell viability with UVA radiation compared to ZnO increased UV absorbance and reduction of Zn2+ release/toxicity(
      • Abadi PG
      • Shirazi FH
      • Joshaghani M
      • Moghimi HR
      Ag(+)-promoted zinc oxide [Zn(O):Ag]: A novel structure for safe protection of human skin against UVA radiation.
      )
      PreventionMetal (zinc)ZnOPeptide modified NPs exhibited lower aggregation

      Reduction in Zn2+ leaching in vitro

      Reduced photocatalytic activity

      Reduced cellular toxicity.

      Better retention in epidermis

      Improved photoprotection.
      (
      • Aditya A
      • Chattopadhyay S
      • Gupta N
      • Alam S
      • Veedu AP
      • Pal M
      • et al.
      ZnO Nanoparticles Modified with an Amphipathic Peptide Show Improved Photoprotection in Skin.
      )
      PreventionMetal (gold)AuAu NPsGold NPs enhance SPF of commercial sunscreens due to reflection and scattering of UV radiation.(
      • Borase HP
      • Patil CD
      • Salunkhe RB
      • Suryawanshi RK
      • Salunke BK
      • Patil SV
      Phytolatex synthesized gold nanoparticles as novel agent to enhance sun protection factor of commercial sunscreens.
      )
      PreventionMetal (silver)AgAg NPsExhibited synergistic increase in SPF of commercial sunscreen and natural extracts with incorporation of AgNPs.(
      • Borase HP
      • Patil CD
      • Suryawanshi RK
      • Patil SV
      Ficus carica latex-mediated synthesis of silver nanoparticles and its application as a chemophotoprotective agent.
      )
      PreventionMetal (zinc)ZnODemonstrated that less than 0.03% of applied Zn content penetrated epidermis no particles could be detected in the lower stratum corneum or viable epidermis via electron microscopy.(
      • Cross SE
      • Innes B
      • Roberts MS
      • Tsuzuki T
      • Robertson TA
      • McCormick P
      Human skin penetration of sunscreen nanoparticles: in-vitro assessment of a novel micronized zinc oxide formulation.
      )
      PreventionMetal (titanium)TiO2TiO2 nanoparticles do not possess post-initiation potential for mouse carcinogenesis (study on safety).(
      • Furukawa F
      • Doi Y
      • Suguro M
      • Morita O
      • Kuwahara H
      • Masunaga T
      • et al.
      Lack of skin carcinogenicity of topically applied titanium dioxide nanoparticles in the mouse.
      )
      PreventionMetal (silver)silverAg NPsAg-NPs are effective in preventing against UVB-induced skin damage(
      • Ho Y-Y
      • Sun D-S
      • Chang H-H
      Silver Nanoparticles Protect Skin from Ultraviolet B-Induced Damage in Mice.
      )
      PreventionMetal (zinc)ZnONano-ZnO able to reach deep layers of allergic skin, bulk-sized ZnO stays in upper layers of both damaged and allergic skin

      Nano-ZnO induced systemic production of IgE Ab
      (
      • Ilves M
      • Palomäki J
      • Vippola M
      • Lehto M
      • Savolainen K
      • Savinko T
      • et al.
      Topically applied ZnO nanoparticles suppress allergen induced skin inflammation but induce vigorous IgE production in the atopic dermatitis mouse model.
      )
      PreventionMetal (titanium)TiO2TiO2 NP in vivo do not penetrate through intact epidermis.(
      • Kiss B
      • Bíró T
      • Czifra G
      • Tóth BI
      • Kertész Z
      • Szikszai Z
      • et al.
      Investigation of micronized titanium dioxide penetration in human skin xenografts and its effect on cellular functions of human skin-derived cells.
      )
      PreventionMetal (titanium)TiO2 coated with ZnOCo-precipitation using TiCl(4) and Zn(NO(3))(2) 6H(2)OTiO2 nanocrystallite powders coated with 9 mol% ZnO has UVA protective capabilities(
      • Ko HH
      • Chen HT
      • Yen FL
      • Lu WC
      • Kuo CW
      • Wang MC
      Preparation of TiO(2) nanocrystallite powders coated with 9 mol% ZnO for cosmetic applications in sunscreens.
      )
      PreventionMetal (zinc)ZnOZnO, coated and uncoatedZnO-NP in viable epidermis did not alter metabolic state or cell morphology

      ZnO NPs are insufficient to affect redox state of viable cells
      (
      • Leite-Silva VR
      • Le Lamer M
      • Sanchez WY
      • Liu DC
      • Sanchez WH
      • Morrow I
      • et al.
      The effect of formulation on the penetration of coated and uncoated zinc oxide nanoparticles into the viable epidermis of human skin in vivo.
      )
      PreventionMetal (titanium)TiO2Modification of surface with carbonModification of TiO2 NP surface with carbon can inhibit photogeneration of free radicals.(
      • Livraghi S
      • Corazzari I
      • Paganini MC
      • Ceccone G
      • Giamello E
      • Fubini B
      • et al.
      Decreasing the oxidative potential of TiO2 nanoparticles through modification of the surface with carbon: a new strategy for the production of safe UV filters.
      )
      PreventionMetal (cerium)cerium oxideExtract of Ziziphus jujube fruitCerium Oxide NPs are nontoxic on cells at concentrations <400 ug/mL after 24 hours

      Offers excellent UV protection
      (
      • Miri A
      • Akbarpour Birjandi S
      • Sarani M
      Survey of cytotoxic and UV protection effects of biosynthesized cerium oxide nanoparticles.
      )
      PreventionMetal (cerium)cerium oxideExhibited SPF ∼40,

      Cerium oxide NPs exhibit non-toxic behavior in concentrations <500 ug/mL on lung cells
      (
      • Miri A
      • Beiki H
      • Najafidoust A
      • Khatami M
      • Sarani M
      Cerium oxide nanoparticles: green synthesis using Banana peel, cytotoxic effect, UV protection and their photocatalytic activity.
      )
      PreventionMetal (gold)AuAu NPsAuNPs are photostable and potential alternative to inorganic sunscreen ingredients

      Environmentally friendly and cost-effective protocol following principles of Green Chemistry
      (
      • Rizzi V
      • Gubitosa J
      • Fini P
      • Nuzzo S
      • Agostiano A
      • Cosma P
      Snail slime-based gold nanoparticles: An interesting potential ingredient in cosmetics as an antioxidant, sunscreen, and tyrosinase inhibitor.
      )
      PreventionMetal (silver)AgAg NPsPretreatment of HaCat cells with AgNPs protected from UVB-irradiation induced apoptosis and reduced CPD formation

      AgNPs were efficiently internalized in UVB-irradiated cells
      (
      • Arora S
      • Tyagi N
      • Bhardwaj A
      • Rusu L
      • Palanki R
      • Vig K
      • et al.
      Silver nanoparticles protect human keratinocytes against UVB radiation-induced DNA damage and apoptosis: potential for prevention of skin carcinogenesis.
      )
      PreventionMetalZinc oxide

      Tio2
      TiO2 and Zn nanoparticles had better spreadability compared to conventional particles

      NPs had higher in vitro SPF compared to conventional particles, suggesting positive effect of reducing particle size on SPF.
      (
      • Singh P
      • Nanda A
      Enhanced sun protection of nano-sized metal oxide particles over conventional metal oxide particles: Anin vitrocomparative study.
      )
      PreventionMetal (titanium)TiO2Modified TiO2 particles retain photocatalytic activity especially in those in which anatase crystal form is present(
      • Tiano L
      • Armeni T
      • Venditti E
      • Barucca G
      • Mincarelli L
      • Damiani E
      Modified TiO(2) particles differentially affect human skin fibroblasts exposed to UVA light.
      )
      PreventionMetal (silica)2-ethylhexyl salicylateHollow silica NPsCovalent attachment with bridged sunscreen monomers reduced leaching and photodegradation over physical encapsulation even with capping(
      • Tolbert SH
      • McFadden PD
      • Loy DA
      New Hybrid Organic/Inorganic Polysilsesquioxane-Silica Particles as Sunscreens.
      )
      PreventionMetalTiO2/Zn2TiO4/Ag nanocompositeNanocomposite prepared using sol-gel methodNanocomposite found to have higher protective factor compared to TiO2 NPs(
      • Torbati TV
      • Javanbakht V
      Fabrication of TiO2/Zn2TiO4/Ag nanocomposite for synergic effects of UV radiation protection and antibacterial activity in sunscreen.
      )
      PreventionMetalZnO

      TiO2

      Ag
      Ag-NPs found to be active in protecting cells against direct UVB damage as well as oxidative DNA damage

      ZnO and TiO2-NPs enhanced oxidative damage via increased ROS production
      (
      • Tyagi N
      • Srivastava SK
      • Arora S
      • Omar Y
      • Ijaz ZM
      • Al-Ghadhban A
      • et al.
      Comparative analysis of the relative potential of silver, Zinc-oxide and titanium-dioxide nanoparticles against UVB-induced DNA damage for the prevention of skin carcinogenesis.
      )
      PreventionMetal (cerium)Cerium oxideNPs prevented human dermal fibroblasts from ROS-induced cell death, stimulated proliferation due to anti-oxidant properties(
      • von Montfort C
      • Alili L
      • Teuber-Hanselmann S
      • Brenneisen P
      Redox-active cerium oxide nanoparticles protect human dermal fibroblasts from PQ-induced damage.
      )
      PreventionMetal (zinc)OxybenzoneZnO nanoparticles made to be the carrier for oxybenzoneOxybenzone almost completely released from ZnO NPs under 2 hrs UV radiation

      Low toxicity to human keratinocyte cells and skin fibroblasts
      (
      • Huang X
      • Wang X
      • Wang S
      • Yang J
      • Zhong L
      • Pan J
      UV and dark-triggered repetitive release and encapsulation of benzophenone-3 from biocompatible ZnO nanoparticles potential for skin protection.
      )
      PreventionMetal (silica)Phenyl motifs (phenylsilane precursors)Ex vivo two-photon microscopy revealed NPs adhere to outer layers of skin with less skin irritation

      In vivo UV protection confirmed excellent sunscreen effect
      (
      • Yoo J
      • Kim H
      • Chang H
      • Park W
      • Hahn SK
      • Kwon W
      Biocompatible Organosilica Nanoparticles with Self-Encapsulated Phenyl Motifs for Effective UV Protection.
      )
      ApplicationCarrierDrugType of NPRemarksAuthors & year
      PreventionPolymerApple peel ethanolic extract (APETE)PLGA nanoparticlesEncapsulation improved stability of APETE

      Demonstrated antioxidant properties
      (
      • Bennet D
      • Kang SC
      • Gang J
      • Kim S
      Photoprotective effects of apple peel nanoparticles.
      )
      PreventionPolymerApigenin (Ap)PLGA nanoparticlesNAp produced better effects than Ap due to their smaller size

      NAp reduced tissue damage and frequency of chromosomal aberrations, increased ROS accumulation to mediate mitochondrial-apoptosis through modulation of several apoptotic markers and mitochondrial matrix swelling

      NAp treated group showed significantly delayed tumor onset.
      (
      • Das S
      • Das J
      • Samadder A
      • Paul A
      • Khuda-Bukhsh AR
      Efficacy of PLGA-loaded apigenin nanoparticles in Benzo[a]pyrene and ultraviolet-B induced skin cancer of mice: mitochondria mediated apoptotic signalling cascades.
      )
      PreventionPolymerPadimate-OPLA-HPGSunblock based on bioadhesive nanoparticles (BNPs) encapsulating PO is persistently adherent and non-penetrant

      BNPs are highly preventive against primary UV-induced damage as well as secondary ROS toxicity.
      (
      • Deng Y
      • Ediriwickrema A
      • Yang F
      • Lewis J
      • Girardi M
      • Saltzman WM
      A sunblock based on bioadhesive nanoparticles.
      )
      PreventionPolymerZinc oxidePEG + chitosanCoating zinc oxide nanoparticles with chitosan and PEG improved photostability and UV absorbance efficacy, and decreased toxicity.(
      • Girigoswami K
      • Viswanathan M
      • Murugesan R
      • Girigoswami A
      Studies on polymer-coated zinc oxide nanoparticles: UV-blocking efficacy and in vivo toxicity.
      )
      PreventionPolymerα-tocopherol, Parsol®MCX (ethylhexyl methoxycinnamate)

      Parsol®1789 (butyl methoxydibenzoylmethane)
      Polyamide nanocoresPolyamide nanocapsules w/ combination of antioxidant and sunscreens

      Encapsulation decreased release rate compared with nano-emulsion

      Minimum penetration through pig ear epidermis and protected against photodegradation
      (
      • Hanno I
      • Anselmi C
      • Bouchemal K
      Polyamide nanocapsules and nano-emulsions containing Parsol® MCX and Parsol® 1789: in vitro release, ex vivo skin penetration and photo-stability studies.
      )
      PreventionPolymerNaringeninPLGANPs exhibited substantial free radical scavenging activity and insignificant cytotoxicity

      Decreased extent of skin permeation, increased skin deposition, and negligible dermal toxicity
      (
      • Joshi H
      • Hegde AR
      • Shetty PK
      • Gollavilli H
      • Managuli RS
      • Kalthur G
      • et al.
      Sunscreen creams containing naringenin nanoparticles: Formulation development and in vitro and in vivo evaluations.
      )
      PreventionPolymerBenzofuroazepine (MBBA)Eudragit® RS 100 as polymeric wall and medium-chain triglyceride or vitamin E as oil coreTested several compounds for encapsulation

      Tested irritant property of encapsulated sunscreen
      (
      • Prado VC
      • Marcondes Sari MH
      • Borin BC
      • do Carmo Pinheiro R
      • Cruz L
      • Schuch A
      • et al.
      Development of a nanotechnological-based hydrogel containing a novel benzofuroazepine compound in association with vitamin E: An in vitro biological safety and photoprotective hydrogel.
      )
      PreventionPolymerbenzofuranoazepineNano-based hydrogel with polymerDemonstrated that the MBBA nanoencapsulation positively influenced its photoprotective effect

      NPs had no in vitro toxicity and mitigated DNA damage induced by exposure to simulated UV radiation
      (
      • Prado VC
      • Marcondes Sari MH
      • Borin BC
      • do Carmo Pinheiro R
      • Cruz L
      • Schuch A
      • et al.
      Development of a nanotechnological-based hydrogel containing a novel benzofuroazepine compound in association with vitamin E: An in vitro biological safety and photoprotective hydrogel.
      )
      PreventionPolymerPLGANPs retained antioxidant effects

      Exhibited better skin retention without permeation
      (
      • Shetty PK
      • Venuvanka V
      • Jagani HV
      • Chethan GH
      • Ligade VS
      • Musmade PB
      • et al.
      Development and evaluation of sunscreen creams containing morin-encapsulated nanoparticles for enhanced UV radiation protection and antioxidant activity.
      )
      PreventionPolymerBenzophenone-3 (ie oxybenzone)PCL coated with chitosan loaded in hydrogelNPs performed well in stratum corneum retention as well as reducing permeation(
      • Siqueira NM
      • Contri RV
      • Paese K
      • Beck RC
      • Pohlmann AR
      • Guterres SS
      Innovative sunscreen formulation based on benzophenone-3-loaded chitosan-coated polymeric nanocapsules.
      )
      PreventionPolymerOctylmethoxycinnamate (OMC)poly(d,l-lactide) nanoparticlesEncapsulation improved photostability without reducing protecting power(
      • Vettor M
      • Perugini P
      • Scalia S
      • Conti B
      • Genta I
      • Modena T
      • et al.
      Poly(D,L-lactide) nanoencapsulation to reduce photoinactivation of a sunscreen agent.
      )
      PreventionPolymerOctyl-methoxycinnamatePLANanoparticle-encapsulated octinoxate exhibited better retention on stratum corneum

      NP demonstrated less penetration in viable skin layers
      (
      • Vettor M
      • Bourgeois S
      • Fessi H
      • Pelletier J
      • Perugini P
      • Pavanetto F
      • et al.
      Skin absorption studies of octyl-methoxycinnamate loaded poly(D,L-lactide) nanoparticles: estimation of the UV filter distribution and release behaviour in skin layers.
      )
      NLCs, as described previously, evolved from SLNs in pursuit of improved encapsulation efficiency and stability in addition to decreased cytotoxicity (
      • Daré RG
      • Costa A
      • Nakamura CV
      • Truiti MCT
      • Ximenes VF
      • Lautenschlager SOS
      • et al.
      Evaluation of lipid nanoparticles for topical delivery of protocatechuic acid and ethyl protocatechuate as a new photoprotection strategy.
      ,
      • Felippim EC
      • Marcato PD
      • Maia Campos PMBG
      Development of Photoprotective Formulations Containing Nanostructured Lipid Carriers: Sun Protection Factor, Physical-Mechanical and Sensorial Properties.
      ). NLCs have been shown to enhance sunscreen photostability and reduce skin irritation. (
      • Damiani E
      • Puglia C
      Nanocarriers and Microcarriers for Enhancing the UV Protection of Sunscreens: An Overview.
      ,
      • Durand L
      • Habran N
      • Henschel V
      • Amighi K
      Encapsulation of ethylhexyl methoxycinnamate, a light-sensitive UV filter, in lipid nanoparticles.
      ,
      • Puglia C
      • Bonina F
      • Rizza L
      • Blasi P
      • Schoubben A
      • Perrotta R
      • et al.
      Lipid nanoparticles as carrier for octyl-methoxycinnamate: in vitro percutaneous absorption and photostability studies.
      ,
      • Suh HW
      • Lewis J
      • Fong L
      • Ramseier JY
      • Carlson K
      • Peng ZH
      • et al.
      Biodegradable bioadhesive nanoparticle incorporation of broad-spectrum organic sunscreen agents.
      ). They have also demonstrated the potential to enhance UV protection, possibly due to their particulate nature, allowing a lower concentration of sunscreens to achieve the same photoprotective effect (
      • Damiani E
      • Puglia C
      Nanocarriers and Microcarriers for Enhancing the UV Protection of Sunscreens: An Overview.
      ,
      • Durand L
      • Habran N
      • Henschel V
      • Amighi K
      Encapsulation of ethylhexyl methoxycinnamate, a light-sensitive UV filter, in lipid nanoparticles.
      ,
      • Wissing S
      Cosmetic applications for solid lipid nanoparticles (SLN).
      ). In one study, incorporation of organic sunscreens into carnauba wax NLCs resulted in SPF values that were 45% higher than the corresponding nanoemulsion. (
      • Nikolić S
      • Keck CM
      • Anselmi C
      • Müller RH
      Skin photoprotection improvement: synergistic interaction between lipid nanoparticles and organic UV filters.
      ) In another study, NLCs encapsulating oxybenzone were shown to increase SPF by more than six-fold while also achieving low skin irritation (
      • Sanad RA
      • Abdelmalak NS
      • Elbayoomy TS
      • Badawi AA
      Formulation of a novel oxybenzone-loaded nanostructured lipid carriers (NLCs).
      ).
      NLCs have also been used in sunscreen formulations that are safer and biorenewable. In 2014, (
      • Niculae G
      • Lacatusu I
      • Bors A
      • Stan R
      Photostability enhancement by encapsulation of α-tocopherol into lipid-based nanoparticles loaded with a UV filter.
      ) published a study in which NLCs were produced from rice bran oil and raspberry seed oil to encapsulate the organic sunscreen agents avobenzone (AVO) and octocrylene (OCR). The NLCs were able to encapsulate a high concentration of both agents (79% AVO and 90% OCR) and, when formulating these NLCs into creams, resulted in an overall sunscreen concentration of only 3.5% (
      • Niculae G
      • Lacatusu I
      • Badea N
      • Stan R
      • Vasile BS
      • Meghea A
      Rice bran and raspberry seed oil-based nanocarriers with self-antioxidative properties as safe photoprotective formulations.
      ). This formulation exhibited improved photoprotection and antioxidant activity.(
      • Niculae G
      • Lacatusu I
      • Badea N
      • Stan R
      • Vasile BS
      • Meghea A
      Rice bran and raspberry seed oil-based nanocarriers with self-antioxidative properties as safe photoprotective formulations.
      ) Antioxidants have also been encapsulated within LNPs with one study showing that NLCs loaded with the antioxidant quercetin, which normally has low stability, exhibited significantly increased in vivo SPF. (
      • Felippim EC
      • Marcato PD
      • Maia Campos PMBG
      Development of Photoprotective Formulations Containing Nanostructured Lipid Carriers: Sun Protection Factor, Physical-Mechanical and Sensorial Properties.
      ) In another study, a sunscreen formulation containing SLNs encapsulating the antioxidant silymarin, a flavonoid, was found to exhibit improved photoprotection. (
      • Netto Mpharm G
      • Jose J
      Development, characterization, and evaluation of sunscreen cream containing solid lipid nanoparticles of silymarin.
      )
      Inorganic NPs, such as nano-sized ZnO and TiO2, have been studied extensively as contributors to an optimized sunscreen formulation (Table 1b). Their nano-sized forms have demonstrated a heightened ability to absorb and scatter UVR, as well as improved spreadability (
      • Singh P
      • Nanda A
      Enhanced sun protection of nano-sized metal oxide particles over conventional metal oxide particles: Anin vitrocomparative study.
      ,
      • Wang SQ
      • Balagula Y
      • Osterwalder U
      Photoprotection: a Review of the Current and Future Technologies.
      ). Given safety concerns surrounding inorganic NPs, attempts have been made to decrease any potential toxicity. One group of researchers coated ZnO NPs with chitosan and PEG, which was shown to improve ZnO stability as well as its photoprotective abilities (
      • Girigoswami K
      • Viswanathan M
      • Murugesan R
      • Girigoswami A
      Studies on polymer-coated zinc oxide nanoparticles: UV-blocking efficacy and in vivo toxicity.
      ). Another study found that using ethylene glycol to modify the surface of TiO2 NPs reduced ROS generation while preserving its sunscreen performance (
      • Livraghi S
      • Corazzari I
      • Paganini MC
      • Ceccone G
      • Giamello E
      • Fubini B
      • et al.
      Decreasing the oxidative potential of TiO2 nanoparticles through modification of the surface with carbon: a new strategy for the production of safe UV filters.
      ). ZnO NPs modified with peptides were found to reduce UVB-induced cellular toxicity and improve epidermal retention.(
      • Aditya A
      • Chattopadhyay S
      • Gupta N
      • Alam S
      • Veedu AP
      • Pal M
      • et al.
      ZnO Nanoparticles Modified with an Amphipathic Peptide Show Improved Photoprotection in Skin.
      ) Aside from ZnO and TiO2, silvericronee (Ag) NPs have also demonstrated photoprotective abilities, particularly against UVB-mediated skin damage in vitro and in vivo as well as oxidative damage (Arora Sumit et al., 2015,
      • Ho Y-Y
      • Sun D-S
      • Chang H-H
      Silver Nanoparticles Protect Skin from Ultraviolet B-Induced Damage in Mice.
      ,
      • Tyagi N
      • Srivastava SK
      • Arora S
      • Omar Y
      • Ijaz ZM
      • Al-Ghadhban A
      • et al.
      Comparative analysis of the relative potential of silver, Zinc-oxide and titanium-dioxide nanoparticles against UVB-induced DNA damage for the prevention of skin carcinogenesis.
      ). Other metals that have been formulated as NPs include cerium and gold, both of which have shown promising results as potential components of sunscreen formulations (
      • Borase HP
      • Patil CD
      • Salunkhe RB
      • Suryawanshi RK
      • Salunke BK
      • Patil SV
      Phytolatex synthesized gold nanoparticles as novel agent to enhance sun protection factor of commercial sunscreens.
      ,
      • Miri A
      • Akbarpour Birjandi S
      • Sarani M
      Survey of cytotoxic and UV protection effects of biosynthesized cerium oxide nanoparticles.
      ,
      • Miri A
      • Beiki H
      • Najafidoust A
      • Khatami M
      • Sarani M
      Cerium oxide nanoparticles: green synthesis using Banana peel, cytotoxic effect, UV protection and their photocatalytic activity.
      ,
      • Rizzi V
      • Gubitosa J
      • Fini P
      • Nuzzo S
      • Agostiano A
      • Cosma P
      Snail slime-based gold nanoparticles: An interesting potential ingredient in cosmetics as an antioxidant, sunscreen, and tyrosinase inhibitor.
      ). Notably, gold NPs are often loaded on polymer and composite carriers due to their high cost and low stability. A combination of metals have also been used in a NP-based sunscreen formulation, as in one study that developed a nanocomposite of TiO2, Zn2TiO4, and silver that was demonstrated to have a higher SPF than TiO2 NPs alone (
      • Torbati TV
      • Javanbakht V
      Fabrication of TiO2/Zn2TiO4/Ag nanocomposite for synergic effects of UV radiation protection and antibacterial activity in sunscreen.
      ).
      Silica-based NPs have been explored as sunscreen formulations. Organosilica NPs have demonstrated photoprotective abilities in vivo with minimal UVR-induced ROS generation. (
      • Yoo J
      • Kim H
      • Chang H
      • Park W
      • Hahn SK
      • Kwon W
      Biocompatible Organosilica Nanoparticles with Self-Encapsulated Phenyl Motifs for Effective UV Protection.
      ) One study encapsulating oxybenzone within mesoporous silica was demonstrated to have enhanced SPF, improved photostability, and decreased skin permeation relative to the unencapsulated form (
      • Li CC
      • Lin YT
      • Chen YT
      • Sie SF
      • Chen-Yang YW
      Improvement in UV protection retention capability and reduction in skin penetration of benzophenone-3 with mesoporous silica as drug carrier by encapsulation.
      ,
      • Walenzyk T
      • Carola C
      • Buchholz H
      • König B
      Synthesis of mono-dispersed spherical silica particles containing covalently bonded chromophores.
      ). Octinoxate was similarly encapsulated within mesoporous silica and found to have improved photoprotective abilities with an increase in SPF of 57% (
      • Chen-Yang YW
      • Chen YT
      • Li CC
      • Yu HC
      • Chuang YC
      • Su JH
      • et al.
      Preparation of UV-filter encapsulated mesoporous silica with high sunscreen ability.
      ).
      The use of polymeric NPs in encapsulating sunscreen agents has been extensively studied (Table 1c). Polymeric NPs have been shown to enhance photoprotective abilities in addition to improving the photostability of various sunscreen agents (
      • Hanno I
      • Anselmi C
      • Bouchemal K
      Polyamide nanocapsules and nano-emulsions containing Parsol® MCX and Parsol® 1789: in vitro release, ex vivo skin penetration and photo-stability studies.
      ,
      • Olvera-Martínez BI
      • Cázares-Delgadillo J
      • Calderilla-Fajardo SB
      • Villalobos-García R
      • Ganem-Quintanar A
      • Quintanar-Guerrero D
      Preparation of polymeric nanocapsules containing octyl methoxycinnamate by the emulsification-diffusion technique: penetration across the stratum corneum.
      ,
      • Perugini P
      • Simeoni S
      • Scalia S
      • Genta I
      • Modena T
      • Conti B
      • et al.
      Effect of nanoparticle encapsulation on the photostability of the sunscreen agent, 2-ethylhexyl-p-methoxycinnamate.
      ). One study that encapsulated OCX in poly(D,L-lactide) NPs found that formulations containing the encapsulated sunscreen agent had improved photostability while maintaining UVB protective effects (
      • Vettor M
      • Perugini P
      • Scalia S
      • Conti B
      • Genta I
      • Modena T
      • et al.
      Poly(D,L-lactide) nanoencapsulation to reduce photoinactivation of a sunscreen agent.
      ). Polymeric NPs have also been demonstrated to decrease skin accumulation of sunscreen agents and the potential of protection against UV-induced erythema (
      • Alvarez-Román R
      • Barré G
      • Guy RH
      • Fessi H
      Biodegradable polymer nanocapsules containing a sunscreen agent: preparation and photoprotection.
      ,
      • Hanno I
      • Anselmi C
      • Bouchemal K
      Polyamide nanocapsules and nano-emulsions containing Parsol® MCX and Parsol® 1789: in vitro release, ex vivo skin penetration and photo-stability studies.
      ,
      • Jiménez MM
      • Pelletier J
      • Bobin MF
      • Martini MC
      Influence of encapsulation on the in vitro percutaneous absorption of octyl methoxycinnamate.
      ,
      • Vettor M
      • Bourgeois S
      • Fessi H
      • Pelletier J
      • Perugini P
      • Pavanetto F
      • et al.
      Skin absorption studies of octyl-methoxycinnamate loaded poly(D,L-lactide) nanoparticles: estimation of the UV filter distribution and release behaviour in skin layers.
      ). Inorganic and organic sunscreen agents have been co-encapsulated. One study co-encapsulating ZnO NPs and OCR within poly(methyl methacrylate) (PMMA) non-degradable NPs exhibited a high encapsulation efficiency and photoprotective properties (
      • Frizzo MS
      • Feuser PE
      • Berres PH
      • Ricci-Júnior E
      • Campos CEM
      • Costa C
      • et al.
      Simultaneous encapsulation of zinc oxide and octocrylene in poly (methyl methacrylate-co-styrene) nanoparticles obtained by miniemulsion polymerization for use in sunscreen formulations.
      ). Antioxidants have also been co-encapsulated with sunscreen agents within polymeric NPs. In 2016, (
      • Hayden DR
      • Imhof A
      • Velikov KP
      Biobased Nanoparticles for Broadband UV Protection with Photostabilized UV Filters.
      ) encapsulated OCX, AVO, and oxybenzone alongside the antioxidant α-tocopherol to improve photostability of the sunscreen agents via scavenging of ROS. Of note, polymers have also been used in sunscreens outside of NPs as film formers, which boost photoprotective properties by increasing water resistance and improving uniformity of application to skin (
      • Osterwalder U
      • Sohn M
      • Herzog B
      Global state of sunscreens.
      ).
      Among the more recent generation of polymeric NPs are bioadhesive NPs (BNPs), particularly the NPs formed from block copolymers of PLA and hyperbranched polyglycerol (PLA-HPG). The bioadhesive property was achieved by converting vicinal diols on the surface of PLA-HPG NPs to aldehydes, which can readily bind amines in proteins via Schiff-base covalent bonding. (
      • Deng Y
      • Ediriwickrema A
      • Yang F
      • Lewis J
      • Girardi M
      • Saltzman WM
      A sunblock based on bioadhesive nanoparticles.
      ) encapsulated padimate-O within biodegradable BNPs. These BNPs exhibited strong adherence to the stratum corneum and water-resistant properties in addition to reducing DNA damage. Building upon the work of Deng et al., (
      • Suh HW
      • Lewis J
      • Fong L
      • Ramseier JY
      • Carlson K
      • Peng ZH
      • et al.
      Biodegradable bioadhesive nanoparticle incorporation of broad-spectrum organic sunscreen agents.
      ) utilized the same BNP delivery system to co-incorporate AVO and OCR, achieving a broad-spectrum sunscreen formulation again exhibiting water-resistant properties as well as effectiveness in protecting against UVR-induced erythema in a pilot clinical study.

      NPs in the treatment of skin cancer

      NPs have been used to treat various types of skin cancer, which can be divided into the two major groups of melanoma and non-melanoma skin cancers (NMSC). NMSC are more common and include squamous cell carcinoma, basal cell carcinoma, Merkel cell carcinoma, and others. Melanoma presents a uniquely different challenge from other forms of skin cancer as it contains both driver and passenger mutations arising from UV irradiation (
      • Thompson JF
      • Scolyer RA
      • Kefford RF
      Cutaneous melanoma.
      ). While primary in situ melanomas are relatively simple to manage with local resection, metastatic melanoma management remains a challenge: the 5 year survival rate with metastatic melanoma has not changed significantly in the past decades (
      • Enninga EAL
      • Moser JC
      • Weaver AL
      • Markovic SN
      • Brewer JD
      • Leontovich AA
      • et al.
      Survival of cutaneous melanoma based on sex, age, and stage in the United States, 1992-2011.
      ). In metastatic melanoma, combination therapy is typically employed with chemotherapy, radiotherapy, immunotherapy including anti PD-1 inhibitors or anti-CTLA-1 inhibitors, and surgery (
      • Johnson DB
      • Nebhan CA
      • Moslehi JJ
      • Balko JM
      Immune-checkpoint inhibitors: long-term implications of toxicity.
      ,
      • Luke JJ
      • Flaherty KT
      • Ribas A
      • Long GV
      Targeted agents and immunotherapies: optimizing outcomes in melanoma.
      ,
      • Tsai S
      • Balch C
      • Lange J
      Epidemiology and treatment of melanoma in elderly patients.
      ).
      Tumor microenvironment (TME) demonstrates a challenging therapeutic target as there is extensive restructuring in tumors with new vasculature, fluid pressure, and extracellular matrix density. Specifically, TMEs are transformed to accommodate the rapid growth of cancerous cells and its differential oxygen and nutritional needs with microenvironments of altered oxygenation, acidity, immunity, metabolism, innervation, and mechanism (
      • Jin MZ
      • Jin WL
      The updated landscape of tumor microenvironment and drug repurposing.
      ). Therefore NPs targeting TME, delivered topically, intradermally, transdermally, or intratumorally, must have improved permeation and penetration with successful accumulation of the drug in the tumor (
      • Krishnan V
      • Mitragotri S
      Nanoparticles for topical drug delivery: Potential for skin cancer treatment.
      ,
      • Mitchell MJ
      • Billingsley MM
      • Haley RM
      • Wechsler ME
      • Peppas NA
      • Langer R
      Engineering precision nanoparticles for drug delivery.
      ). Hypoxia also plays a large role in tumorigenesis and shaping of the TME with increased angiogenesis in larger, solid tumors. Additionally, TME is intrinsically acidic due to the Warburg effect in which tumorigenic environments have extensive metabolic reprogramming with increased glucose consumption and dependence on lactic dehydrogenase pathway. The main challenge in therapeutic delivery for skin cancer treatment is to improve the selectivity of anticancer drugs for TME while sparing healthy cells.
      When delivered systemically, larger molecules and NPs can accumulate in tumors via the enhanced permeability and retention effect (EPR); EPR effect describes the concept in which leaky tumor vasculature and poor lymphatic clearance in tumors allows for accumulation of these molecules in the tumor (
      • Kumar Giri T
      • Giri A
      • Kumar Barman T
      • Maity S
      Nanoliposome is a Promising Carrier of Protein and Peptide Biomolecule for the Treatment of Cancer.
      ,
      • Nakamura Y
      • Mochida A
      • Choyke PL
      • Kobayashi H
      Nanodrug Delivery: Is the Enhanced Permeability and Retention Effect Sufficient for Curing Cancer?.
      ,
      • Song M
      • Xia W
      • Tao Z
      • Zhu B
      • Zhang W
      • Liu C
      • et al.
      Self-assembled polymeric nanocarrier-mediated co-delivery of metformin and doxorubicin for melanoma therapy.
      ,
      • van der Meel R
      • Sulheim E
      • Shi Y
      • Kiessling F
      • Mulder WJM
      • Lammers T
      Smart cancer nanomedicine.
      ). The EPR effect is applicable in intravenous injection of nanoparticles; the longer the drugs are in circulation encapsulated in the NPs, they can extravasate into the tumors due to the EPR effect (
      • Nakamura Y
      • Mochida A
      • Choyke PL
      • Kobayashi H
      Nanodrug Delivery: Is the Enhanced Permeability and Retention Effect Sufficient for Curing Cancer?.
      ). Employing NPs for delivery can theoretically increase retention in tumor sites via EPR and allow better tolerability of such cytotoxic drugs while decreasing the necessity for large surgical reconstructions.
      Topical and transdermal delivery of NPs is also frequently employed. As mentioned above, topical delivery is challenged by the dense stratum corneum requiring either an already damaged skin surface for the NPs absorption and delivery or creation of micropores for delivery of NPs (
      • Tadros AR
      • Romanyuk A
      • Miller IC
      • Santiago A
      • Noel RK
      • O'Farrell L
      • et al.
      STAR particles for enhanced topical drug and vaccine delivery.
      ). Microneedles have also been employed for NP delivery as they can penetrate the epidermis and enter the dermis; these are typically patches with extremely fine needles loaded with NPs to painlessly penetrate the epidermis (
      • Hao Y
      • Chen Y
      • He X
      • Yang F
      • Han R
      • Yang C
      • et al.
      Near-infrared responsive 5-fluorouracil and indocyanine green loaded MPEG-PCL nanoparticle integrated with dissolvable microneedle for skin cancer therapy.
      ,
      • Prausnitz MR
      Engineering Microneedle Patches for Vaccination and Drug Delivery to Skin.
      ,
      • Prausnitz MR
      • Langer R
      Transdermal drug delivery.
      ). They are especially advantageous in cancer therapeutics as it can induce skin-homing immune cells and improve antitumor immunity (
      • Balmert SC
      • Carey CD
      • Falo GD
      • Sethi SK
      • Erdos G
      • Korkmaz E
      • et al.
      Dissolving undercut microneedle arrays for multicomponent cutaneous vaccination.
      ,
      • Korkmaz E
      • Balmert SC
      • Sumpter TL
      • Carey CD
      • Erdos G
      • Falo Jr., LD
      Microarray patches enable the development of skin-targeted vaccines against COVID-19.
      ).
      NP strategies for gene therapy, while beyond the scope of this review, have been extensively characterized, including for use in the treatment of solid tumors (
      • Chen J
      • Guo Z
      • Tian H
      • Chen X
      Production and clinical development of nanoparticles for gene delivery.
      ,
      • Choi YS
      • Lee MY
      • David AE
      • Park YS
      Nanoparticles for gene delivery: therapeutic and toxic effects.
      ,
      • Dizaj SM
      • Jafari S
      • Khosroushahi AY
      A sight on the current nanoparticle-based gene delivery vectors.
      ,
      • Lee YS
      • Kim SW
      Bioreducible polymers for therapeutic gene delivery.
      ,
      • Pérez-Herrero E
      • Fernández-Medarde A
      Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy.
      ). Briefly, NP based carriers for small interfering RNA (siRNA), peptide conjugated siRNA (PNA), gene, and other RNA interference have been used to leverage the capacity of NPs to protect such agents from hydrolytic and enzymatic cleavage (
      • Chen J
      • Dong X
      • Feng T
      • Lin L
      • Guo Z
      • Xia J
      • et al.
      Charge-conversional zwitterionic copolymer as pH-sensitive shielding system for effective tumor treatment.
      ). Discussion below of examples of particles for skin cancer treatment highlight recent works that go beyond encapsulation of a therapeutic with engineered properties that target the TME.
      Table 2 includes published examples of various anticancer therapeutics encapsulated in NPs. As previously mentioned, both topical and intratumoral delivery of NPs have been tried with lipid-based NPs (Table 2a) (
      • Geetha T
      • Kapila M
      • Prakash O
      • Deol PK
      • Kakkar V
      • Kaur IP
      Sesamol-loaded solid lipid nanoparticles for treatment of skin cancer.
      ,
      • Iqubal MK
      • Iqubal A
      • Imtiyaz K
      • Rizvi MMA
      • Gupta MM
      • Ali J
      • et al.
      Combinatorial lipid-nanosystem for dermal delivery of 5-fluorouracil and resveratrol against skin cancer: Delineation of improved dermatokinetics and epidermal drug deposition enhancement analysis.
      ,
      • Krishnan V
      • Mitragotri S
      Nanoparticles for topical drug delivery: Potential for skin cancer treatment.
      ,
      • Palliyage GH
      • Hussein N
      • Mimlitz M
      • Weeder C
      • Alnasser MHA
      • Singh S
      • et al.
      Novel Curcumin-Resveratrol Solid Nanoparticles Synergistically Inhibit Proliferation of Melanoma Cells.
      ). For instance, resveratrol, which has demonstrated in vitro and in vivo antioxidant and tumoricidal effects has shown limited clinical efficacy, most likely due to its limited penetrance. Zhao et al. and Iqubal et al have demonstrated that lipid-based NP encapsulation of resveratrol significantly improves its antitumor activity and improves skin penetration (
      • Iqubal MK
      • Iqubal A
      • Imtiyaz K
      • Rizvi MMA
      • Gupta MM
      • Ali J
      • et al.
      Combinatorial lipid-nanosystem for dermal delivery of 5-fluorouracil and resveratrol against skin cancer: Delineation of improved dermatokinetics and epidermal drug deposition enhancement analysis.
      ,
      • Zhao YN
      • Cao YN
      • Sun J
      • Liang Z
      • Wu Q
      • Cui SH
      • et al.
      Anti-breast cancer activity of resveratrol encapsulated in liposomes.
      ).(
      • Iqubal MK
      • Iqubal A
      • Imtiyaz K
      • Rizvi MMA
      • Gupta MM
      • Ali J
      • et al.
      Combinatorial lipid-nanosystem for dermal delivery of 5-fluorouracil and resveratrol against skin cancer: Delineation of improved dermatokinetics and epidermal drug deposition enhancement analysis.
      ) has demonstrated an engineered solid lipid NP to improve skin permeation of 5-fluorouracil and resveratrol, which have both been used clinically but with difficulty in penetrating the stratum corneum.
      Table 2Applications of Nanoparticles for Skin Cancer Treatment, Table 2a – Lipid nanoparticles for Skin Cancer Treatment. Table 2b – Polymeric nanoparticles for Skin Cancer Treatment. Table 2c – Polymeric nanoparticles for Skin Cancer Treatment. Table 2d – Organic nanoparticles for Skin Cancer Treatment
      ApplicationCarrierDrugType of NPModelRemarksAuthor & year
      Treatmentsolid lipidItraconazoleSLN with cationic outer shellin vitro A431, SKMEL5, and HaCaTDrug release study and in vitro cytotoxicity study(
      • Carbone C
      • Martins-Gomes C
      • Pepe V
      • Silva AM
      • Musumeci T
      • Puglisi G
      • et al.
      Repurposing itraconazole to the benefit of skin cancer treatment: A combined azole-DDAB nanoencapsulation strategy.
      )
      TreatmentLiposomeModified viral (HPV-16 E7 peptide, RF9)

      Self-peptide Ags
      Cationic lipid enantiomerSeveral in vivo models; for skin cancer B16F10Tumor regression study performed

      Observed several immunologic studies to demonstrate CD8 induction and type II IFN pathway induction

      Demonstrated the combinatorial effect of the liposome with anti PD-1 therapy
      (
      • Gandhapudi SK
      • Ward M
      • Bush JPC
      • Bedu-Addo F
      • Conn G
      • Woodward JG
      Antigen Priming with Enantiospecific Cationic Lipid Nanoparticles Induces Potent Antitumor CTL Responses through Novel Induction of a Type I IFN Response.
      )
      TreatmentLiposomeSesamolSolid lipid nanoparticleNormal mice skin compared to those exposed to carcinogen with or without different treatments.Topical application of SLN in a cream base to determine retention in the skin

      Demonstrated the delay in skin cancer development with NP
      (
      • Geetha T
      • Kapila M
      • Prakash O
      • Deol PK
      • Kakkar V
      • Kaur IP
      Sesamol-loaded solid lipid nanoparticles for treatment of skin cancer.
      )
      TreatmentLiposome5-fluorouracil

      Resveratrol
      Solid lipid nanoparticles (SLN)Study of mechanism of skin permeation enhancement, dermatokinetic assessment, and depth analysis of optimized formulation on skin

      Exhibited improved permeation and distribution of drugs to the dermis layer of skin
      (
      • Iqubal MK
      • Iqubal A
      • Imtiyaz K
      • Rizvi MMA
      • Gupta MM
      • Ali J
      • et al.
      Combinatorial lipid-nanosystem for dermal delivery of 5-fluorouracil and resveratrol against skin cancer: Delineation of improved dermatokinetics and epidermal drug deposition enhancement analysis.
      )
      TreatmentLiposome5-FUSLNin vivo - Erhlich's skin tumorHistopathology to demonstrate that application of SLN-loaded 5-FU increased the penetration capability of 5-FU(
      • Khallaf RA
      • Salem HF
      • Abdelbary A
      5-Fluorouracil shell-enriched solid lipid nanoparticles (SLN) for effective skin carcinoma treatment.
      )
      TreatmentLiposomeMethotrexate (MTX)Lipid nanoparticle with conjugated hylauronic acidin vivo melanoma B16F10Demonstrated the effects of HA Mw on cell binding, immune response, circulation time and tumor localization as well as therapeutic response

      Demonstrated antitumor efficacy with MTX as encapsulated therapeutic
      (
      • Mizrahy S
      • Goldsmith M
      • Leviatan-Ben-Arye S
      • Kisin-Finfer E
      • Redy O
      • Srinivasan S
      • et al.
      Tumor targeting profiling of hyaluronan-coated lipid based-nanoparticles.
      )
      TreatmentLiposomeIL-12 mRNA

      IL-27 mRNA
      Diamino LNPsIn vitro and in vivo melanoma B16F10DAL-LNPs are effective in delivering mRNA to lead to cytokine expressions

      I.t. delivery lead to slowed tumor growth and increased tumor infiltrating lymphocytes and expression of cytokines
      (
      • Liu JQ
      • Zhang C
      • Zhang X
      • Yan J
      • Zeng C
      • Talebian F
      • et al.
      Intratumoral delivery of IL-12 and IL-27 mRNA using lipid nanoparticles for cancer immunotherapy.
      )
      TreatmentLiposomeDNA vaccine encoding melanoma tumor-associated antigen (pCMV-MART1)Cationic lipidsin vitro and in vivo melanoma B16F10Melanoma vaccination study

      Tumor regression study, cytokine release study from cocultured splenocytes of transfected mice with their particle to demonstrate antitumor efficacy
      (
      • Moku G
      • Vangala S
      • Gulla SK
      • Yakati V
      In vivo Targeting of DNA Vaccines to Dendritic Cells via the Mannose Receptor Induces Long-Lasting Immunity against Melanoma.
      )
      TreatmentLiposomeCurcumin (Cur)

      Resveratrol (Res)
      Solid lipid nanoparticle (SLN)in vitro melanoma (B16F10) but only in the context that of overcoming mechanical forces on the cellMore than 70% of Cur-Res SLNs were bound to skin locally in a skin binding study (using snake skin)

      Utility of Cur-Res SLNs in the treatment of localized melanoma.
      (
      • Palliyage GH
      • Hussein N
      • Mimlitz M
      • Weeder C
      • Alnasser MHA
      • Singh S
      • et al.
      Novel Curcumin-Resveratrol Solid Nanoparticles Synergistically Inhibit Proliferation of Melanoma Cells.
      )
      TreatmentLiposomePaclitaxel; PTX siRNA (Bcl-2)R-DOTAP solid lipid nanoparticlein vitro melanoma B16F10To overcome the multidrug resistance by silencing Bcl-2 protein and increase the therapeutic efficacy of PTX

      Group performed uptake study with in vitro models by observing uptake of siRNA in addition to cell cycle arrest after delivery of BCL-2 siRNA
      (
      • Reddy TL
      • Garikapati KR
      • Reddy SG
      • Reddy BVS
      • Yadav JS
      • Bhadra U
      • et al.
      Simultaneous delivery of Paclitaxel and Bcl-2 siRNA via pH-Sensitive liposomal nanocarrier for the synergistic treatment of melanoma.
      )
      TreatmentLiposomeDoxorubicinSolid lipid nanoparticlein vitro and in vivo melanoma B16F10FTIR spectroscopy was used to study the possible drug–excipient interaction and basically drug release

      Group demonstrated persistent effect of Dox-SLN up to 72 hours
      (
      • Tupal A
      • Sabzichi M
      • Ramezani F
      • Kouhsoltani M
      • Hamishehkar H
      Dermal delivery of doxorubicin-loaded solid lipid nanoparticles for the treatment of skin cancer.
      )
      TreatmentLiposomeOil of Zataria multiflora (ZMSLN)Solid-lipid nanoparticles (SLN)in vitro melanoma A375EOs are generally hydrophobic

      Loading EOs into nanocarriers improved their performance
      (
      • Valizadeh A
      • Khaleghi AA
      • Roozitalab G
      • Osanloo M
      High anticancer efficacy of solid lipid nanoparticles containing Zataria multiflora essential oil against breast cancer and melanoma cell lines.
      )
      TreatmentLiposomeTopotecanSLNFull thickness porcine ear skin and in vitro melanoma B16F10Particle characterization with size and PDI, in vitro release assay, drug permeation study using the porcine ear

      Cytotoxicity study with melanoma cells
      (
      • Venancio JH
      • Andrade LM
      • Esteves NLS
      • Brito LB
      • Valadares MC
      • Oliveira GAR
      • et al.
      Topotecan-loaded lipid nanoparticles as a viable tool for the topical treatment of skin cancers.
      )
      ApplicationCarrierDrugType of NPModelRemarksAuthors & year
      TreatmentPolymerBromelainPLGA nanoparticlesInduced tumorigenesis using DMBA + TPA on the dorsal surface of micePrevention of tumor formation on mice with NP application

      DNA alkaline unwinding assay to demonstrate antitumor effect
      (
      • Bhatnagar P
      • Pant AB
      • Shukla Y
      • Chaudhari B
      • Kumar P
      • Gupta KC
      Bromelain nanoparticles protect against 7,12-dimethylbenz[a]anthracene induced skin carcinogenesis in mouse model.
      )
      TreatmentPolymerIL-12PEGylated hyaluronic acid nanogel (NI-MAHA-PEG nanogel)in vivo melanoma B16F10Environment responsive NP with increased drug release in hypoxic environment, demonstrated with drug release study

      Demonstrated distribution of nanoparticles with IVIS

      Demonstrate NP antitumor efficacy
      (
      • Zhang C
      • Li Q
      • Wu C
      • Wang J
      • Su M
      • Deng J
      Hypoxia-responsive nanogel as IL-12 carrier for anti-cancer therapy.
      )
      TreatmentPolymerDocetaxel (DTX)

      Zinc-phthalocyanine (ZnPc)
      PEO2000–PCL6800–PEO2000 triblock copolymer (ABA format)in vivo melanoma A375Hemolysis was assessed in the NP concentration range from 0.01 to 2.0 mg/mL, with and without cryoprotector

      NPs did not display significant hemolysis in vivo model that received photosensitizer with the docetaxel were also with phototherapy for evaluation of antitumor efficacy
      (
      • Conte C
      • Ungaro F
      • Maglio G
      • Tirino P
      • Siracusano G
      • Sciortino MT
      • et al.
      Biodegradable core-shell nanoassemblies for the delivery of docetaxel and Zn(II)-phthalocyanine inspired by combination therapy for cancer.
      )
      TreatmentPolymerApigeninPLGA nanoparticlesin vitro melanoma - A375 and skin keratinocyte cell line HaCaTAssessed for mitochondrial apoptosis in in vitro melanoma(
      • Das S
      • Das J
      • Samadder A
      • Paul A
      • Khuda-Bukhsh AR
      Strategic formulation of apigenin-loaded PLGA nanoparticles for intracellular trafficking, DNA targeting and improved therapeutic effects in skin melanoma in vitro.
      )
      TreatmentPolymerDacarbazine (DTIC) in the core

      Conjugation with TRAIL-receptor 2 (DR5) monoclonal antibody (mAb)
      PLA core nanoparticlein vitro melanoma A375Determined amount of DR5 mAb bound conjugated on the surface

      Studied NP functionality by assessing cytotoxicity against the A375 cell line
      (
      • Ding B
      • Wu X
      • Fan W
      • Wu Z
      • Gao J
      • Zhang W
      • et al.
      Anti-DR5 monoclonal antibody-mediated DTIC-loaded nanoparticles combining chemotherapy and immunotherapy for malignant melanoma: target formulation development and in vitro anticancer activity.
      )
      TreatmentPolymerCamptothecinPLA-HPGin vivo SCC PDVC57Demonstrated the particle "stickiness" with poly-l-lysine coated slides

      Demonstrated intratumoral retention of drug with a time course study

      Efficacy against in vivo SCC model
      (
      • Hu JK
      • Suh HW
      • Qureshi M
      • Lewis JM
      • Yaqoob S
      • Moscato ZM
      • et al.
      Nonsurgical treatment of skin cancer with local delivery of bioadhesive nanoparticles.
      )
      TreatmentPolymerCoumarin-scopoletin (7-hydroxy-6-methoxy coumarin, HMC, C(10)H(8)O(4))polylactic-co-glycolic acid (PLGA)in vitro melanoma A375In vitro cytotoxicity and ICD study with cells incubated with NPs(
      • Khuda-Bukhsh AR
      • Bhattacharyya SS
      • Paul S
      • Boujedaini N
      Polymeric nanoparticle encapsulation of a naturally occurring plant scopoletin and its effects on human melanoma cell A375.
      )
      TreatmentPolymerMertansinecRGD-decorated polymersomal mertansine prodrug (cRGD-PS-DM1)in vitro and in vivo melanoma B16F10Confocal to assess particle uptake by B16 cells in vitro, also in vivo antitumoral effect(
      • Meng H
      • Zou Y
      • Zhong P
      • Meng F
      • Zhang J
      • Cheng R
      • et al.
      A Smart Nano-Prodrug Platform with Reactive Drug Loading, Superb Stability, and Fast Responsive Drug Release for Targeted Cancer Therapy.
      )
      TreatmentPolymer + metal5-FUalbumin, poly(lactic-co-glycolic acid) (PLGA), magnetic nanoparticles (10 nm) and fluorescent labeling molecule (diphenylhexatriene).in vivo SCCPenetration study of the DDS into the tumor tissue and H&E of tumor were analyzed on each harvested tumor

      Higher concentration of the DDS was noted in the DDS + magnet group implying the magnetic force aided the DDS in penetrating the boundary between the subcutaneous and tumor tissue
      (
      • Misak H
      • Zacharias N
      • Song Z
      • Hwang S
      • Man KP
      • Asmatulu R
      • et al.
      Skin cancer treatment by albumin/5-Fu loaded magnetic nanocomposite spheres in a mouse model.
      )
      TreatmentPolymer + metalAlbumin and 5-FUPLGA and magnetic nanoparticle (Magnetite)in vivo SCCPenetration of the particle into tumor tissue determined with H&E stained tumor

      Magnet used to draw the particles into the tumor to increase efficacy of 5-FU
      (
      • Misak H
      • Zacharias N
      • Song Z
      • Hwang S
      • Man KP
      • Asmatulu R
      • et al.
      Skin cancer treatment by albumin/5-Fu loaded magnetic nanocomposite spheres in a mouse model.
      )
      TreatmentPolymer + metalDoxorubicinPEGlyated platinum nanoparticlesin vitro melanoma B16F10 and A549; In vivo melanoma B16F10In vitro cell viability assay and ex vivo CEA assay to determine material biocompatibility

      In vitro antitumor effect determined with incubation with the particles

      H&E of tumors after injection also done to look at SOX2 and KI67 expression. TUNEL assay with tumor apoptosis done to determine therapeutic delivery
      (
      • Mukherjee S
      • Kotcherlakota R
      • Haque S
      • Bhattacharya D
      • Kumar JM
      • Chakravarty S
      • et al.
      Improved delivery of doxorubicin using rationally designed PEGylated platinum nanoparticles for the treatment of melanoma.
      )
      TreatmentPolymernovel tubulin inhibitor, 2-(1H-indol-5-yl)thiazol-4-yl)3,4,5-trimethoxyphenyl methanoneMethoxy polyethylene glycol-b-poly(carbonate-co-lactide) (mPEG-b-P(CB-co-LA))in vitro melanoma - A375 and B16F10 cell; in vivo melanoma B16F10Observed in vitro cell cycle arrest after incubation of B16 cells with nanoparticles + drug

      In vivo study for efficacy against metastatic melanoma
      (
      • Mundra V
      • Peng Y
      • Kumar V
      • Li W
      • Miller DD
      • Mahato RI
      Systemic delivery of nanoparticle formulation of novel tubulin inhibitor for treating metastatic melanoma.
      )
      TreatmentPolymerMetformin (MET)

      Doxorubicin (DOX)
      Folic acid-cholesterol-sodium alginate NPsin vivo Melanoma xenograft A380NPs injected into Xenograft melanoma tumors demonstrated anti-melanoma effects

      Found that FCA NP-loaded MET&DOX triggered PANoptosis of melanoma cells in vitro and in vivo
      (
      • Song M
      • Xia W
      • Tao Z
      • Zhu B
      • Zhang W
      • Liu C
      • et al.
      Self-assembled polymeric nanocarrier-mediated co-delivery of metformin and doxorubicin for melanoma therapy.
      )
      TreatmentPolymerCyanine IR-768, a photosensitizer

      Daunorubicin
      Methoxypoly(ethylene oxide)-b-poly(lactide-co-glycolide) (mPEG-b-PLGA)in vitro melanoma A375 and keratinocytesMitochondria targeting properties by polymeric micelles

      Efficient singlet oxygen generation contributed to strong phototoxic effect induced in vitro
      (
      • Tokarska K
      • Lamch L
      • Piechota B
      • Zukowski K
      • Chudy M
      • Wilk KA
      • et al.
      Co-delivery of IR-768 and daunorubicin using mPEG-b-PLGA micelles for synergistic enhancement of combination therapy of melanoma.
      )
      TreatmentPolymerImiquimod

      Copaiba oil
      Poly (ε-caprolactone) (PCL)in vitro keratinocyte HaCaTWhen imiquimod is nanoencapsulated, it does not influence keratinocyte HaCaT cell viability

      Purpose of the study is not to reduce tumor growth but rather make imiquimod more tolerable and stable
      (
      • Venturini CG
      • Bruinsmann FA
      • Contri RV
      • Fonseca FN
      • Frank LA
      • D'Amore CM
      • et al.
      Co-encapsulation of imiquimod and copaiba oil in novel nanostructured systems: promising formulations against skin carcinoma.
      )
      TreatmentPolymerGly–Arg–Gly–Asp–Ser (GRGDS) peptidesMBCSPs consist of a thermo-responsive shell of poly(N-isopropylacrylamide–acrylamide–allylamine) and a core of PLGA with magnetite.in vivo melanoma B16F10Particles were accumulated at the tumor site in a melanoma orthotopic mouse model, especially in the presence of a magnet(
      • Wadajkar AS
      • Bhavsar Z
      • Ko CY
      • Koppolu B
      • Cui W
      • Tang L
      • et al.
      Multifunctional particles for melanoma-targeted drug delivery.
      )
      TreatmentPolymerCpGPEIin vivo melanoma B16F10Dendritic cell maturation and ELISA study of supernatant to demonstrate in vitro generation of immunogenic response

      Assessed intratumoral immune response
      (
      • Xu E
      • Saltzman WM
      • Piotrowski-Daspit AS
      Escaping the endosome: assessing cellular trafficking mechanisms of non-viral vehicles.
      )
      TreatmentPolymerPaclitaxel in the core

      IL-2 within the "shell"
      poly (lactic-co-glycolic acid) (PLGA)/Pluronic F127in vitro and in vivo melanoma B16F10To develop the synergistic effect of immunochemotherapy

      Determined the dose of chemotherapy necessary to potentiate CpG effect

      Immune cell populations in tumor were studied
      (
      • Zhao Y
      • Song Q
      • Yin Y
      • Wu T
      • Hu X
      • Gao X
      • et al.
      Immunochemotherapy mediated by thermosponge nanoparticles for synergistic anti-tumor effects.
      )
      TreatmentPolymerα-Mangostin (αM)monomethoxy poly (ethylene glycol)-polycaprolactones (MPEG-PCLs)in vitro melanoma B16F10 and A375, in vivo melanoma A375in vivo antitumor efficacy determined

      IHC of the tumor cross section with TUNEL assay and CD31 performed
      (
      • Yang S
      • Gao X
      • He Y
      • Hu Y
      • Xu B
      • Cheng Z
      • et al.
      Applying an innovative biodegradable self-assembly nanomicelles to deliver alpha-mangostin for improving anti-melanoma activity.
      )
      TreatmentPolymeric liposomeanti-CD137 and an IL-2-Fc fusionPEGlyated liposomesin vivo melanoma B16F10 and B16F10-Trp2KOTested the utility of nanoparticle-IL-2/anti-CD137 to rapidly accumulate in tumors while minimizing systemic exposure

      Demonstrated anti-tumor effect and reduced lung metastasis burden without signs of systemic toxicity
      (
      • Zhang Y
      • Li N
      • Suh H
      • Irvine DJ
      Nanoparticle anchoring targets immune agonists to tumors enabling anti-cancer immunity without systemic toxicity.
      )
      ApplicationCarrierDrugType of NPModelRemarksAuthors & year
      TreatmentMetal (Cerium)Cerium oxidein vitro melanoma A375in vitro markers of ICD

      Study on possible adverse effects of CeO2 nanoparticles along with their toxic potential low cytotoxic and genotoxic effects in A375 cells
      (
      • Ali D
      • Alarifi S
      • Alkahtani S
      • AlKahtane AA
      • Almalik A
      Cerium Oxide Nanoparticles Induce Oxidative Stress and Genotoxicity in Human Skin Melanoma Cells.
      )
      TreatmentMetal (cerium)Cerium oxidecerium oxide nanoparticles (CNPs)in vitro and in vivo melanoma A375Significant lowered tumor growth was observed for both applications of CNPs

      Melanoma cells were incubated and the cell proliferation was analyzed by MTT assays observed other markers of ICD in vitro
      (
      • Alili L
      • Sack M
      • von Montfort C
      • Giri S
      • Das S
      • Carroll KS
      • et al.
      Downregulation of tumor growth and invasion by redox-active nanoparticles.
      )
      TreatmentMetal (silver)BSABSA/AgNP-loaded hydrogel filmin vivo melanoma B16F10Bioadhesiveness of the BSA/AgNP gel film was measured against pig skin

      In vivo and in vitro photosensitizer study were performed tumor sections of the mice with PTT at 50°C showed significant loss of cancer cells
      (
      • Amatya R
      • Hwang S
      • Park T
      • Chung YJ
      • Ryu S
      • Lee J
      • et al.
      BSA/Silver Nanoparticle-Loaded Hydrogel Film for Local Photothermal Treatment of Skin Cancer.
      )
      TreatmentMetalEtoposide

      Methotrexate
      Fe3O4-Ag2O QDs/Cellulose Fibers Nanocompositesin vitro melanoma B16in vitro cytotoxicity study

      Drug release profile

      Free drug scavenging activity
      (
      • Fakhri A
      • Tahami S
      • Nejad PA
      Preparation and characterization of Fe3O4-Ag2O quantum dots decorated cellulose nanofibers as a carrier of anticancer drugs for skin cancer.
      )
      TreatmentMetal and MembraneOncolytic virus Ad5Lecithin and cholesterol and CaCl2in vitro and in vivo melanoma B16F10Tested efficacy, safety, accuracy and mechanism of Lipo-Cap–Ad5 combined with PD-1 inhibitors in vivo

      Tumor infiltration of immune cells determined
      (
      • Ji W
      • Li L
      • Zhou S
      • Qiu L
      • Qian Z
      • Zhang H
      • et al.
      Combination immunotherapy of oncolytic virus nanovesicles and PD-1 blockade effectively enhances therapeutic effects and boosts antitumour immune response.
      )
      TreatmentMetal (silica)ErianinDendritic mesoporous silica nanospheresin vitro human immortalized keratinocyte (HaCaT) cells, ex vivo Porcine skinCellular uptake study, in vitro release study, and cellular proliferation study performed

      Apoptosis in vitro determined

      Detected cytoplasmic calcium concentration with western blot

      Porcine skin retention and penetration study with the drug performed
      (
      • Mo C
      • Lu L
      • Liu D
      • Wei K
      Development of erianin-loaded dendritic mesoporous silica nanospheres with pro-apoptotic effects and enhanced topical delivery.
      )
      TreatmentMetal (cerium)DoxorubicinRedox-active cerium oxide nanoparticles (CNP)in vitro melanoma A375CNP uptake in melanoma cells; cell viability after incubation with doxorubicin loaded CNP

      Measurement of ROS of cells incubated with doxorubicin-CNP
      (
      • Sack M
      • Alili L
      • Karaman E
      • Das S
      • Gupta A
      • Seal S
      • et al.
      Combination of conventional chemotherapeutics with redox-active cerium oxide nanoparticles--a novel aspect in cancer therapy.
      )
      TreatmentMetal (gold)Fluorouracil (5-FU)Gold nanoparticles capped with cetyltrimethylammonium bromide (CTAB)in vivo Human epidermoid carcinoma A431 cellsSmall and positively charged GNPs had high skin permeability

      5-FU GNPs cream and gel were significantly efficacious in inhibiting tumor growth
      (
      • Safwat MA
      • Soliman GM
      • Sayed D
      • Attia MA
      Fluorouracil-Loaded Gold Nanoparticles for the Treatment of Skin Cancer: Development, in Vitro Characterization, and in Vivo Evaluation in a Mouse Skin Cancer Xenograft Model.
      )
      TreatmentMetal (silica) and hylauronCarboplatinSilica NP with hyaluronic acid conjugatedin vivo melanoma A375Enzymatic activity of hyaluronic acid quantified

      Performed in vivo tumor NP studies with the particles
      (
      • Scodeller P
      • Catalano PN
      • Salguero N
      • Duran H
      • Wolosiuk A
      • Soler-Illia GJ
      Hyaluronan degrading silica nanoparticles for skin cancer therapy.
      )
      TreatmentMetal (silver) and polymer5-aminolevulinic acid (5-ALA)PEGylated silver nanoparticlesin vitro melanoma B16 and in vitro epidermoid carcinoma (human) A431Antibacterial and antifungal activity of silver nanoparticles were studied(
      • Shivashankarappa A
      • Sanjay KR
      Photodynamic therapy on skin melanoma and epidermoid carcinoma cells using conjugated 5-aminolevulinic acid with microbial synthesised silver nanoparticles.
      )
      TreatmentMetal (iron) and polymerChlorin e6 (Ce6) and doxorubicin conjugated to PEGPolyglycerol-Coated Iron Oxidein vitro and in vivo melanoma B16F10NP treated cells exhibited substantial nuclear presence of γH2AX staining

      Expression and/or emission of DAMPs was assayed

      In vivo tumors received NP and irradiation

      Tumor were harvested, and expression of DAMPs and type-1 macrophage activation markers were analyzed
      (
      • Li TF
      • Xu HZ
      • Xu YH
      • Yu TT
      • Tang JM
      • Li K
      • et al.
      Efficient Delivery of Chlorin e6 by Polyglycerol-Coated Iron Oxide Nanoparticles with Conjugated Doxorubicin for Enhanced Photodynamic Therapy of Melanoma.
      )
      TreatmentMetal (iron) and polymerChlorin e6 (photosensitizer for PDT) loaded, doxorubicin attached to the PG coatingIron oxide nanoparticles coated with polyglycerol (PG)In vitro and in vivo melanoma B16F10ROS, apoptosis, and cellular uptake studied in vitro

      In vivo models were treated with the particles and the tumors received laser irradiation

      Tumors harvested and IHC stained to determine photoinduced DAMP and type-I activation of macrophages

      Blood clearance kinetic and organ distribution study performed
      (
      • Li TF
      • Xu HZ
      • Xu YH
      • Yu TT
      • Tang JM
      • Li K
      • et al.
      Efficient Delivery of Chlorin e6 by Polyglycerol-Coated Iron Oxide Nanoparticles with Conjugated Doxorubicin for Enhanced Photodynamic Therapy of Melanoma.
      )
      Protection & TreatmentMetal (gold)Sorafenib (multi-kinase inhibitor)Gold nanoparticles (AuNPs)in vitro HUVEC; in vivo with melanoma B16F10Evaluation of tumor blood vessel perfusion, permeability and hypoxia.

      CD31 staining for neoangiogenesis

      Observed decreased vascular formation with delivery and regulation of VEGF

      Tested tumor mesenchymal transition and potential normalization of tumor vasculature with the treatment
      (
      • Huang W
      • Xing Y
      • Zhu L
      • Zhuo J
      • Cai M
      Sorafenib derivatives-functionalized gold nanoparticles confer protection against tumor angiogenesis and proliferation via suppression of EGFR and VEGFR-2.
      )
      TreatmentMetal (zinc)Doxorubicinsilica-coated gold NPs ([email protected] NPs) + zinc oxidein vitro and in vivo melanoma B16Cytotoxicity and photothermal therapy in vitro with 655 nm laser demonstrated

      Used asynchronous bilateral tumor inoculation to assess abscopal effect with NP treated tumors with slowed tumor growth
      (
      • Zhang Y
      • Guo C
      • Liu L
      • Xu J
      • Jiang H
      • Li D
      • et al.
      ZnO-based multifunctional nanocomposites to inhibit progression and metastasis of melanoma by eliciting antitumor immunity via immunogenic cell death.
      )
      TreatmentLipid - calcium - polymerCpG ODN and p-Trp2Mannose-PEG - LCP NPs with CaP corein vivo melanoma B16F10Lymph nodes from mice injected were harvested for distribution study

      IFN-γ production induced by the tumor antigen was analyzed

      Demonstrated reduced tumor growth with NP
      (
      • Xu Z
      • Ramishetti S
      • Tseng YC
      • Guo S
      • Wang Y
      • Huang L
      Multifunctional nanoparticles co-delivering Trp2 peptide and CpG adjuvant induce potent cytotoxic T-lymphocyte response against melanoma and its lung metastasis.
      )
      TreatmentLipid - calcium - polymerTrp2 peptide (melanoma speicifc antigen) and CpGLipid/ calcium/ phosphate nanoparticlein vitro B16F10In vivo tumor growth inhibition and metastasis inhibition determined

      IFN-g production determined by in vitro study of harvested spleen and lymph nodes from mice vaccinated with the particles

      In vivo cytotoxic T lymphocyte assay determined by immunizing mice with different formulations and harvesting spleen and determining CFSE and Trp2 specific lysis
      (
      • Xu Z
      • Ramishetti S
      • Tseng YC
      • Guo S
      • Wang Y
      • Huang L
      Multifunctional nanoparticles co-delivering Trp2 peptide and CpG adjuvant induce potent cytotoxic T-lymphocyte response against melanoma and its lung metastasis.
      )
      TreatmentMetal (graphene) and polysaccharideDacarbazine and anti-CD47Nano-sized graphene oxide (nGO) modified with chitosan oligosaccharide (COS)in vitro melanoma B16F10In vitro cytotoxicity tests performed including determination of ROS generation, mitochondrial membrane potential, and apoptosis(
      • Zhan X
      • Teng W
      • Sun K
      • He J
      • Yang J
      • Tian J
      • et al.
      CD47-mediated DTIC-loaded chitosan oligosaccharide-grafted nGO for synergistic chemo-photothermal therapy against malignant melanoma.
      )
      TreatmentMetal (graphene) and PolysaccharideDacarbazine encapsulated and CD47 antibody conjugated outsideChitosan grafted nanographene oxide (nGO)in vitro melanoma B16F10CD47 receptor mediated endocytosis of the particles

      In vitro cytotoxicity and cell death induction determined by B16 cell incubation with particles then with photothermal irradiation
      (
      • Zhan X
      • Teng W
      • Sun K
      • He J
      • Yang J
      • Tian J
      • et al.
      CD47-mediated DTIC-loaded chitosan oligosaccharide-grafted nGO for synergistic chemo-photothermal therapy against malignant melanoma.
      )
      ApplicationCarrierDrugType of NPModelRemarksAuthors & year
      TreatmentPolysaccharideFucoxanthinLipidic nanocarrier coated with chitosanCellular uptake with human fibroblast and psoriasis like cellular modelParticle characterized by Xray power diffraction

      Bioadhesion measurement performed to "damage skin" as modeled by eggshell membrane

      Psoriatic like cellular model created by incubating the keratinocyte with cytokine to induce cellular differentiation similar to psoriasis

      Biocompatibility and fibroblast uptake determined
      (
      • Cordenonsi LM
      • Faccendini A
      • Catanzaro M
      • Bonferoni MC
      • Rossi S
      • Malavasi L
      • et al.
      The role of chitosan as coating material for nanostructured lipid carriers for skin delivery of fucoxanthin.
      )
      TreatmentPolysaccharide (chitosan)S-nitrosomercaptosuccinic acidChitosan nanoparticlesin vitro melanoma B16F10Cytotoxic study with MTT

      LDH release of cells determined with LDH assay kit

      Active caspase 3 measured after incubation of the cells with NPs

      Reduced protein thiol content measured
      (
      • Ferraz LS
      • Watashi CM
      • Colturato-Kido C
      • Pelegrino MT
      • Paredes-Gamero EJ
      • Weller RB
      • et al.
      Antitumor Potential of S-Nitrosothiol-Containing Polymeric Nanoparticles against Melanoma.
      )
      TreatmentMembrane/ vesiclecell penetrating peptide (CPP) conjugatedhepatitis B virus-like nanoparticles (VLNPs)in vitro SCC A431Particle internalization property studied

      Determined that there is energy dependent endocytosis.
      (
      • Gan BK
      • Yong CY
      • Ho KL
      • Omar AR
      • Alitheen NB
      • Tan WS
      Targeted Delivery of Cell Penetrating Peptide Virus-like Nanoparticles to Skin Cancer Cells.
      )
      TreatmentMembrane/ vesicle/ virus like particleCpG A type with peptidevirus-like nanoparticlesNAT cell frequencies determined in the patients after vaccination study

      Determined safety and T cell frequencies

      PET/CT studies of lymph nodes of patients. Analysis of tumor tissue from patients with relapse
      (
      • Goldinger SM
      • Dummer R
      • Baumgaertner P
      • Mihic-Probst D
      • Schwarz K
      • Hammann-Haenni A
      • et al.
      Nano-particle vaccination combined with TLR-7 and -9 ligands triggers memory and effector CD8⁺ T-cell responses in melanoma patients.
      )
      TreatmentMembrane/ polysaccharideYeast derived particle (beta glucan)in vivo melanoma B16F10Yeast cell wall of different sizes and characterized

      Determined activation of immune cells including DCs and macrophages

      Compared particles of different sizes and their in vivo antitumor activity and TME and TDLN changes

      Determined the accumulation of NP to TDLNs

      Determined NP activity when paired with PD-1 antagonist for metastatic melanoma
      (
      • Xu J
      • Ma Q
      • Zhang Y
      • Fei Z
      • Sun Y
      • Fan Q
      • et al.
      Yeast-derived nanoparticles remodel the immunosuppressive microenvironment in tumor and tumor-draining lymph nodes to suppress tumor growth.
      )
      TreatmentPolysaccharide5-fluorouracilchitosan-folate submicron particles (folic acid as the targeting ligand)in vitro skin permeation study with healthy male Sprague Dawley rats; in vitro melanoma cells SKMEL28Microwave radiation enhanced drug permeation transdermally with no significant temperature rise on skin

      Drug release, permeation, retention and particle morphology, and in vitro skin diffusion tested in vitro cytotoxicity study performed
      (
      • Nawaz A
      • Wong TW
      Chitosan-Carboxymethyl-5-Fluorouracil-Folate Conjugate Particles: Microwave Modulated Uptake by Skin and Melanoma Cells.
      )
      TreatmentPolysaccharideSN38 (camptothecin chemotherapeutic)Dermatan sulfate chitosan nanocarrier (natural glycosaminoglycan)in vitro and in vivo melanoma B16F10SN38/DCNP distributed to the tumor by the EPR effect and binding to CD146 on the surface of melanoma cells

      Particles demonstrated pH triggered degradability

      In vivo tumor efficacy also determined with TUNEL assay
      (
      • Li S
      • Zhang F
      • Yu Y
      • Zhang Q
      A dermatan sulfate-functionalized biomimetic nanocarrier for melanoma targeted chemotherapy.
      )
      TreatmentMembrane/ vesicle (virus derived)Melanoma-specific Melan-A/Mart-1 peptide

      CpG
      virus-like nanoparticlesNATrafficking of the particles was performed with in vivo imaging

      Melanoma patients vaccinated with the particles had detectable CD8 T cells with activation determined by PBMC
      (
      • Speiser DE
      • Schwarz K
      • Baumgaertner P
      • Manolova V
      • Devevre E
      • Sterry W
      • et al.
      Memory and effector CD8 T-cell responses after nanoparticle vaccination of melanoma patients.
      )
      TreatmentPolysaccharideBSA p53Chitosan-tripolyphosphate nanoparticleIn vitro human melanoma SKMel28Cellular uptake of the particles by human skin melanoma cells was evaluated by fluorescence microscopy and gel electrophoresis.(
      • Stie MB
      • Thoke HS
      • Issinger OG
      • Hochscherf J
      • Guerra B
      • Olsen LF
      Delivery of proteins encapsulated in chitosan-tripolyphosphate nanoparticles to human skin melanoma cells.
      )
      TreatmentMembrane/ vesicleDIR

      Doxorubicin
      lipophilic fluorescent probe and nanovesiclein vitro and in vivo melanoma B16F10Nanovesical property, drug loading, and in vitro drug release and in vitro photothermal release were determined

      The biodistribution of injected formulations at various time points was monitored

      In vivo anti tumor efficacy determined.
      (
      • Wu T
      • Zhang D
      • Qiao Q
      • Qin X
      • Yang C
      • Kong M
      • et al.
      Biomimetic Nanovesicles for Enhanced Antitumor Activity of Combinational Photothermal and Chemotherapy.
      )
      TreatmentPolysaccharidesDocetaxel-cystamine prodrug (DTX-cys)Chondroitin sulfate (amphiphilic polymer)in vivo melanoma B16F10Redox responsive prodrug to target tumor tissues In vitro cancer cell apoptosis and cellular uptake study performed with dye loaded particles

      In vivo tumors and normal tissues were analyzed by H&E
      (
      • Li TF
      • Xu HZ
      • Xu YH
      • Yu TT
      • Tang JM
      • Li K
      • et al.
      Efficient Delivery of Chlorin e6 by Polyglycerol-Coated Iron Oxide Nanoparticles with Conjugated Doxorubicin for Enhanced Photodynamic Therapy of Melanoma.
      )
      TreatmentMembrane/ vesiclesulforaphanebroccoli membranein vitro melanoma SKMEL28A proteomic analysis was carried out to qualitatively evaluate the proteins present in the BM-vesicles

      The cytotoxic effect of BM-vesicles at different concentrations was evaluated

      Cellular penetration of both the drug and the membrane performed
      (
      • Yepes-Molina L
      • Carvajal M
      Nanoencapsulation of sulforaphane in broccoli membrane vesicles and their in vitro antiproliferative activity.
      )
      TreatmentPolysaccharidePhenophobideEmulsan shell and hydrophobic oil core (emulsan is a biosurfactant from a bacterial RAG-1)in vivo SCC SCC7SCC cell viability determined after incubation with particle

      In vivo imaging performed with IVIS

      Ex vivo analysis of dissected organs and tumor tissues performed after injection in vivo SCC models, injection of NPs followed by laser irradiation led to tumor death
      (
      • Yi G
      • Son J
      • Yoo J
      • Park C
      • Koo H
      Emulsan-based nanoparticles for in vivo drug delivery to tumors.
      )
      Graphics
      Graphics are created with BioRender.com.
      Liposomes and LNPs have the capacity to incorporate several agents of different characteristics, including peptides and nucleic acids, with great stability. (
      • Gandhapudi SK
      • Ward M
      • Bush JPC
      • Bedu-Addo F
      • Conn G
      • Woodward JG
      Antigen Priming with Enantiospecific Cationic Lipid Nanoparticles Induces Potent Antitumor CTL Responses through Novel Induction of a Type I IFN Response.
      ) have employed conjugation of peptides to target tumor-associated antigens that are commonly expressed in human skin tumors. Cytokines, one of the first immunotherapies in cancer therapeutics, can also be delivered with decreased systemic toxicity in lipid-based NPs. When delivered as a systemic monotherapy, cytokines are significantly limited due to facile degradation and dose-limiting toxicity and side effects. In a study by (
      • Liu JQ
      • Zhang C
      • Zhang X
      • Yan J
      • Zeng C
      • Talebian F
      • et al.
      Intratumoral delivery of IL-12 and IL-27 mRNA using lipid nanoparticles for cancer immunotherapy.
      ), LNPs encapsulating IL-12 and IL-27 cytokine mRNA were efficacious in low toxicity antitumor therapy against melanoma. Previously limited by the small therapeutic window, antitumoral cytokine IL-12 when paired with anti-inflammatory IL-27 led to significant anti-tumor responses in in-vivo models without signs of systemic toxicity nor inflammation. Lastly, LNPs have also been used to demonstrate smaller segments of nucleic acids such as siRNA. (
      • Reddy TL
      • Garikapati KR
      • Reddy SG
      • Reddy BVS
      • Yadav JS
      • Bhadra U
      • et al.
      Simultaneous delivery of Paclitaxel and Bcl-2 siRNA via pH-Sensitive liposomal nanocarrier for the synergistic treatment of melanoma.
      ) aimed to overcome multidrug resistance and increase the therapeutic efficacy of paclitaxel, a well-studied chemotherapy agent, by co-delivery with Bcl-2 siRNA. The encapsulation allowed for improved uptake of siRNA and demonstrated cell cycle arrest after delivery of BCL-2 siRNA.
      The capability of R-DOTAP as a carrier to deliver immunotherapy was studied by (
      • Gandhapudi SK
      • Ward M
      • Bush JPC
      • Bedu-Addo F
      • Conn G
      • Woodward JG
      Antigen Priming with Enantiospecific Cationic Lipid Nanoparticles Induces Potent Antitumor CTL Responses through Novel Induction of a Type I IFN Response.
      ). Using an LNP, modified viral or self-peptide Ags and melanoma associated peptide Trp2 were loaded and delivered intratumorally in animal models of melanoma. One injection of formulated LNPs caused complete regression in various solid tumor models including melanoma; there was significant induction of cytotoxic T cells to induce type I and type II IFN pathway to induce priming of antitumor immunity. By remodeling the TME and the immune microenvironment, they were able to achieve good combinatorial therapy and antitumor effect when LNP was administered with anti PD-1.
      Lipid-based NP surfaces are also often modified to improve tumor localization. (
      • Mizrahy S
      • Goldsmith M
      • Leviatan-Ben-Arye S
      • Kisin-Finfer E
      • Redy O
      • Srinivasan S
      • et al.
      Tumor targeting profiling of hyaluronan-coated lipid based-nanoparticles.
      ) studied the conjugation of hyaluronan to lipid-based NP. Effects of various low, medium, and high hyaluronan molecular weight conjugated to lipid NPs were studied to determine how the conjugation molecule characteristics would affect cell binding, immunogenicity, circulation time, and tumor localization. They had demonstrated that small molecular weight hyaluronic acid was most effective in targeting tumors HA coated lipid NP demonstrated high affinity towards HA receptors on tumor cells both in vitro and in vivo and against melanoma. Loading methotrexate into the HA lipid NPs demonstrated enhanced therapeutic response in comparison to free methotrexate and lipid NP with methotrexate without hyaluronan conjugation.
      Because of their synthetic versatility, high encapsulation efficiency, and stability, polymeric NPs have increased in popularity as new carriers for treatment of non-melanoma and melanoma skin cancer (Table 2b). (
      • Hu JK
      • Suh HW
      • Qureshi M
      • Lewis JM
      • Yaqoob S
      • Moscato ZM
      • et al.
      Nonsurgical treatment of skin cancer with local delivery of bioadhesive nanoparticles.
      ) have demonstrated a polymeric NP with aldehyde modification on the surface that improved bioadhesion to the tumor matrix due to formation of Schiff bonds. Camptothecin delivery via NPs increased intratumoral drug retention in addition to therapeutic efficacy against in vivo squamous cell carcinoma: the aldehyde modification on the outershell demonstrated that bioadhesion to the tumor matrix significantly improved the antitumor effect and increased survival in preclinical model of SCC.
      Coencapsulation of agents such as immunotherapy and chemotherapy is a common strategy in polymer NP drug delivery, providing synergistic antitumor effect. Combining immunotherapy with chemotherapeutics can improve cancer therapy by providing a cell death signal, enhancing antitumor immunogenicity that is further potentiated with immune stimulation (
      • Dong K
      • Li Z
      • Sun H
      • Ju E
      • Ren J
      • Qu X
      Pathogen-mimicking nanocomplexes: self-stimulating oxidative stress in tumor microenvironment for chemo-immunotherapy.
      ,
      • Ramakrishnan R
      • Gabrilovich DI
      Novel mechanism of synergistic effects of conventional chemotherapy and immune therapy of cancer.
      ,
      • Shankaran V
      • Ikeda H
      • Bruce AT
      • White JM
      • Swanson PE
      • Old LJ
      • et al.
      IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity.
      ). For instance, (
      • Zhao Y
      • Song Q
      • Yin Y
      • Wu T
      • Hu X
      • Gao X
      • et al.
      Immunochemotherapy mediated by thermosponge nanoparticles for synergistic anti-tumor effects.
      ) created a polymeric NP composed of PLGA to co-deliver paclitaxel in conjunction with immunostimulant IL-2 to potentiate the immune tumor response in melanoma. Interestingly, co-encapsulation of dual therapeutic methods significantly decreased tumor growth in comparison to two separate, individual NPs with encapsulated paclitaxel and IL-2. The cytokine responses significantly differed between single drug and dual drug encapsulation with reduction of TGF-b and IL-10 level and increased IFN-gamma and IL-12 with combinatorial therapy compared to free agents and single drug encapsulation. Co-encapsulation demonstrated therapeutic efficacy against metastatic melanoma spread with combinatorial NP with IL-2 and paclitaxel, outperforming free agents and single encapsulated NP agents.
      PEGylation of NPs of different cores has also been employed to decrease early uptake and degradation. A study has demonstrated anchoring the surface of liposomes with PEGylation and conjugation with anti-CD137 can allow for rapid accumulation of the particles in tumors while decreasing systemic toxicity (
      • Zhang Y
      • Li N
      • Suh H
      • Irvine DJ
      Nanoparticle anchoring targets immune agonists to tumors enabling anti-cancer immunity without systemic toxicity.
      ). Though cytokine therapy with IL-2 had previously demonstrated efficacy against several solid tumors including melanoma, there was significant toxicity due to cytokine storm through nonspecific, systemic lymphocyte stimulation. PEGylated liposomal delivery of CD137 and IL-2 fusion achieved significantly decreased tumor size and improved survival against in vivo melanoma and decreasing metastatic melanoma spread.
      PEGylation has been extensively employed for environment-responsive NP delivery. One study demonstrated a TME responsive PEGylated hyaluronic acid nanogel that would release drugs in hypoxia (
      • Zhang C
      • Li Q
      • Wu C
      • Wang J
      • Su M
      • Deng J
      Hypoxia-responsive nanogel as IL-12 carrier for anti-cancer therapy.
      ). IL-12, a cytokine with antitumor activity and induction of innate and adaptive immunity through activation of NK cells, T cells, and thus release of IFN-gamma, was encapsulated in this nanogel. While a powerful immunostimulant with anti-tumor activity, systemic administration of IL-12 has been associated with significant side effects which limits its current use in clinical settings. The release of particles and IL-12 in acidic and hypoxic conditions was demonstrated. In vivo studies demonstrated the ability of the targeted delivery system to decrease systemic circulation and accumulation of IL-12 after administration demonstrating its antitumor efficacy and on-demand release in TME.
      Metal-based NPs are often used for applications of PDT or PDT combined with chemotherapy in which NPs are injected or applied to the cutaneous site and irradiated with lasers locally (Table 2c). In one application, Ag NPs were topically applied for PTT via a hydrogel patch to improve synthesis and bioadhesiveness (
      • Amatya R
      • Hwang S
      • Park T
      • Chung YJ
      • Ryu S
      • Lee J
      • et al.
      BSA/Silver Nanoparticle-Loaded Hydrogel Film for Local Photothermal Treatment of Skin Cancer.
      ). For cutaneous skin malignancies, hydrogel patches have been effective for PTT delivery without necessitating intratumoral injection. A hydrogel film with BSA and silver NPs with low dose laser irradiation provided effective energy for laser-induced cell death and impeded melanoma growth in vivo.
      Thermo-chemotherapy delivery with mesoporous silica NPs have also been well studied. However, given limitations with conventional metal nanoparticle related to nonspecific drug delivery, premature drug release, and lack of prolonged antitumor immunogenicity, a pH sensitive mesoporous silica-coated gold NPs were developed by (
      • Zhang Y
      • Guo C
      • Liu L
      • Xu J
      • Jiang H
      • Li D
      • et al.
      ZnO-based multifunctional nanocomposites to inhibit progression and metastasis of melanoma by eliciting antitumor immunity via immunogenic cell death.
      ). The group demonstrated that a pH-responsive, mesoporous silica coated gold NPs loaded with doxorubicin can effectively deliver chemotherapy to acidic environments. When the tumor site was irradiated with 655 nm laser at various time intervals and power densities, there was significant tumor growth inhibition with combination therapy with both chemotherapy and laser irradiation significantly improving tumor growth inhibition in comparison to single therapy. This combination therapy demonstrated effective induction of immunogenic cell death, maturation of antigen presenting cells, and infiltration into primary and metastatic melanoma.
      Organically derived NP cancer therapy has rapidly progressed in the last decade (Table 2d). These are often used for loading of immunotherapies as they potentiate well with the virus-like NPs or those derived from vesicles/membranes. Indeed, there have already been clinical phase I/II studies in stage II-IV melanoma patients to observe the effect of virus-like NPs loaded with Type A CpG. In these studies, patients were injected with particles as vaccinations, either subcutaneously or intradermally, and induction of Type I IFN along with maturation of dendritic cells and cytotoxic T cell differentiation was studied (
      • Goldinger SM
      • Dummer R
      • Baumgaertner P
      • Mihic-Probst D
      • Schwarz K
      • Hammann-Haenni A
      • et al.
      Nano-particle vaccination combined with TLR-7 and -9 ligands triggers memory and effector CD8⁺ T-cell responses in melanoma patients.
      ,
      • Speiser DE
      • Schwarz K
      • Baumgaertner P
      • Manolova V
      • Devevre E
      • Sterry W
      • et al.
      Memory and effector CD8 T-cell responses after nanoparticle vaccination of melanoma patients.