The principal function of skin is to defend our body from external pathogens as a topical bander and is exploited for cutaneous and percutaneous delivery of therapeutics considering the advantageous bypassing of first pass metabolism and patient compliance. Based on the structure of SC, it could be highlighted that the skin integrity, dimensions of orifices, aqueous pores, lipidic fluid paths, and the density of appendages affect the absorption of topically applied therapeutic agents (Baroli, 2010). The major routes of penetration through the skin barrier include the intercellular lipid route and transcellular or transappendageal (follicular) pathways (Paliwal, 2017). Nanocarriers interact with skin based on size, surface charge, lamellarity, and mode of application and can translocate intact into the skin without being degraded or they can be degraded near the skin surface and the incorporated therapeutic molecule can penetrate into skin layers. However, most particles do not cross the SC and the transappendageal route appears to be the dominant pathway of NP entry into skin irrespective of the nanomaterial.

Chitin is a natural polysaccharide like CS that has been exploited for various biomedical applications, and its positive charge aids in its use as a skin penetration enhancer. Sabitha et al. reported the use of chitin in the form of nanogels for the transdermal delivery of anticancer molecules like curcumin (Mangalathillam et al., 2012) and 5-FU (Sabitha et al., 2013) for melanoma. They developed 70-80 nm curcumin-loaded chitin nanogels (CCNGs) and 120-140-nm-sized 5-FU-loaded chitin nanogels (FCNGs), which were found to be effective against melanoma cell lines (A-375) in vitro. Ex vivo penetration studies performed in porcine skin showed a fourfold increase in steady-state transdermal flux of curcumin from CCNGs as compared to that of the control curcumin solution. FCNGs showed more or less similar steady-state flux as that of control 5-FU, but the retention in the deeper layers of skin was found to be 4-5 times more. Histopathological evaluation revealed loosening of the outer most layer of epidermis, SC, by interaction of catatonically charged chitin, with no observed signs of inflammation; hence, nanogels could be a good option for treatment of skin cancers (Mangalathillam et al., 2012; Sabitha et al., 2013). Many studies are reported for the use of CS NPs for transdermal drug delivery. Recently, transdermal drug delivery mechanisms of CS NPs with the synergistic action of microwave in skin modification was investigated by Nawaz and Wong (2017). The transdermal drug delivery profiles of 5-FU-loaded CS NPs across untreated and microwave-treated skin were examined. The drug transport was mediated via NPs carrying drug across the skin and/or diffusion of earlier-released drug molecules from skin surfaces. The CS NPs largely affected the palmitic acid and keratin domains. Combined microwave and nanotechnologies synergize polysaccharide-mediated transdermal drug delivery (Nawaz and Wong, 2017).

The skin comprising a linear polysaccharide HA is being investigated as a topical delivery carrier in recent times. The properties of HA that aid skin permeability include the following: (1) it is a hygroscopic polyanion, (2) it has the ability to hydrate the skin, (3) the hydrophobic patch of HA interacts with the lipid components in SC during penetration and disrupt the skin barriers, and (4) the presence of HA receptors on the skin resident cells (keratinocytes in epidermis and fibroblasts in the dermis over expressed HA receptors) (Kim, 2014). A nanographene oxide HA conjugate (NGO-HA) was synthesized for phototlrermal ablation therapy of melanoma skin cancer using a near-infrared (NIR) laser. The transdermal delivery of NGO-HA was enhanced by the EPR effect and the overexpressed HA receptors around the tumor tissues. The NIR irradiation resulted in complete ablation of tumor with no recurrence of tumorigenesis in tissues (Jung et al., 2013). Lee et al. (2016) reported the targeted delivery of death receptor 5 antibody-conjugated hyaluronate-gold nanorod (HA-AuNRDR5 Ab) for the transdermal tlreranosis of skin cancer. Wang et al. (2018) worked on polysaccharide-based microneedles for the sustained delivery of anti-(PDl) for immunotherapy of cancer. They used pH-sensitive dextran NPs integrated with biocompatible HA that encapsulated aPDl and glucose oxidase (GOx), which converts blood glucose to gluconic acid. Altering the pH of the environment to acidic promotes the self-dissociation of NPs and subsequently results in the substantial release of aPDl. They reported immediate immune responses in a B16F10 mouse melanoma model with a single administration of the microneedle patch (Wang et al., 2018).

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