Xinxin Li,1,2,* Chunsheng Yang,3,4,* Yingkai Tao,1,2 Xiaoyang Hou,1,2 Yanqun Liu,1,2 Hong Sang,3 Guan Jiang1,2 1Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, 221004, People’s Republic of China; 2Department of Dermatology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, People’s Republic of China; 3Jinling Hospital Department of Dermatology, Nanjing Medical University, Nanjing, 210002, People’s Republic of China; 4Department of Dermatology, The Affiliated Huai’an Hospital of Xuzhou Medical University, The Second People’s Hospital of Huai’an, Huai’an, 223002, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hong SangJinling Hospital Department of Dermatology, Nanjing Medical University, Nanjing, 210002, People’s Republic of ChinaEmail sanghong@nju.edu.cnGuan JiangDepartment of Clinical Medicine, Xuzhou Medical University, Xuzhou, 221004, People’s Republic of ChinaEmail dr.guanjiang@xzhmu.edu.cnPurpose: A near-infrared (NIR)-triggered trans-activating transcriptional activator (TAT)-based targeted drug delivery system for the combined chemo/photothermal therapy of melanoma, namely, TAT-TSL-TMZ (temozolomide)/IR820, was developed for the first time.Methods: TAT-TSL-TMZ/IR820 liposomes were synthesized via thin-film dispersion and sonication. IR820 and TMZ were encased in the inner layer and lipid bilayer of the liposomes, respectively.Results: Dynamic light scattering results showed that the liposomes had an average hydrodynamic size of 166.9 nm and a zeta potential of − 2.55 mV. The encapsulation rates of TMZ and IR820 were 35.4% and 28.6%, respectively. The heating curve obtained under near-infrared (NIR) laser irradiation showed that TAT-TSL-TMZ/IR820 liposomes had good photothermal conversion efficiency. The in vitro drug release curve revealed that NIR laser irradiation could accelerate drug release from TAT-TSL-TMZ/IR820 liposomes. The results of inverted fluorescence microscopy and flow cytometry proved that the uptake of TAT-TSL-TMZ/IR820 liposomes by human melanoma cells (MV3 cells) was concentration-dependent and that the liposomes modified with membrane peptides were more likely to be ingested by cells than unmodified liposomes. Confocal laser scanning microscopy indicated that TAT-TSL-TMZ/IR820 liposomes entered MV3 cells via endocytosis and was stored in lysosomes. In addition, TAT-TSL-TMZ/IR820 liposomes exposed to NIR laser showed 89.73% reduction in cell viability.Conclusion: This study investigated the photothermal conversion, cell uptake, colocation and chemo/photothermal effect of TAT-TSL-TMZ/IR820 liposomes.Keywords: melanoma, liposome, TAT, photothermal therapy, temozolomide, IR820