▎ 摘　　要

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-trypto-phan-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 ab-scopal 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.(c) 2022 Elsevier Ltd. All rights reserved.