Lipo/TK-CDN/TPP/Y6 nanoparticles inhibit cutaneous melanoma formation

Stimulation of the innate immune stimulator of interferon genes (STING) pathway has been shown to boost anti-tumor immunity. Nevertheless, the systemic delivery of STING agonists to the tumor presents challenges. Therefore, we designed a cyclic dinucleotide (CDN)-based drug delivery system (DDS) combined photothermal (PTT)/photodynamic (PDT)/immunotherapy for cutaneous melanoma. We coencapsulated a reactive oxygen species (ROS)-responsive prodrug thioketone-linked CDN (TK-CDN), and photoresponsive agents chlorin E6 (Y6) within mitochondria-targeting reagent triphenylphosphonium (TPP)-modified liposomes (Lipo/TK-CDN/TPP/Y6). Lipo/TK-CDN/TPP/Y6 exhibited a photothermal effect similar to Y6, along with a superior cellular uptake rate. Upon endocytosis by B16F10 cells, Lipo/TK-CDN/TPP/Y6 generated large amounts of ROS under laser irradiation for PDT. Mice bearing B16F10 tumors were intravenously injected with Lipo/TK-CDN/TPP/Y6 and exposed to irradiation, resulting in a substantial inhibition of tumor growth. Exploration of the mechanism of anti-tumor action showed that Lipo/TK-CDN/TPP/Y6 had a stronger stimulation of STING activation and anti-tumor immune cell infiltration compared to other groups. Hence, the Lipo/TK-CDN/TPP/Y6 nanoparticles offer great potential as a DDS for targeted and on-demand drug release at tumor sites. These nanoparticles exhibit promise as a candidate for precise and controllable combination therapy in the treatment of tumors.