Transdermal delivery system based on heparin-modified graphene oxide for deep transportation, tumor microenvironment regulation, and immune activation

Enhancing skin penetration and facilitating tumor infiltration in melanoma treatment through transdermal administration remains an intractable challenge. In the present study, docetaxel- and 1-methyl-D-tryptophan-loaded heparin-modified graphene oxide (D-1/GH) nanosheets were developed to overcome these barriers. Through heparin (Hep)-mediated stratum corneum (SC) hydration, D-1/GH permeates the skin through the intercellular route and the appendage pathway. Based on the relatively leaky structure of the tumor and the high affinity of Hep for tumors, D-1/GH can infiltrate tumors. Subsequently, D-1/GH is transported to deeper tumors through blood and lymphatic vessels. Theoretically, D-1/GH is wrapped in lymphatic vessels through the lymphatic vessel endothelial receptor-1 (LYVE-1)-mediated lymphatic transmigratory cup structure and enters blood vessels through the enhanced permeation and retention (EPR) effect, which is reported here for the first time. D-1/GH-mediated combinational therapy augments the therapeutic effect of chemotherapy and photothermal therapy (PTT) while inducing immunogenic cell death (ICD), thereby recruiting immune cells, and eliciting an immune response. D-1/GH reverses the immunosuppressive tumor microenvironment to potentiate the immune response, thus suppressing abscopal tumors and lung metastases. Collectively, this study identified a novel permeation mode, providing a new perspective to improve antitumor efficacy, boost immune response, and avert systemic distribution.

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