A Multifunctional Nanoparticle Dual Loading with Chlorin e6 and STING Agonist for Combinatorial Therapy of Melanoma.

Photodynamic therapy (PDT) is a noninvasive therapeutic approach that is effective in killing primary tumors with minimal surgical trauma, but its usage in metastatic lesions of melanoma is restricted by spatial limitations. Recently, stimulator of interferon genes (STING) agoinst-mediated innate immunity can activate the STING pathway and further promote dendritic cell (DC) maturation, tumor-specific cytotoxic T lymphocyte, and natural killer cell infiltration and has emerged as a promising approach for cancer therapy. Herein, the authors intriduce facile nanoparticles named HTCS, which can co-deliver STING agonist (2'3'-cGAMP) and a mitochondrial targeting modified photosensitizer (TPP-PEI-Ce6). While HTCS were intravenously injected to mice, they were endocytosed into tumor cells through hyaluronic acid-mediated active targeting. Thereafter, TPP-PEI-Ce6 was delivered to mitochondria to generate a large variety of reactive oxygen species and killed tumor cells effectively. Then the tumor cell debris further gave rise to immunogenic cell death, which played a role in immunosuppression. Furthermore, 2'3'-cGAMP contained in cell debris activated the STING pathway to promote the release of inflammatory cytokines and the maturation of DCs. As a consequence, the HTCS could achieve photodynamic multiple immunotherapy for melanoma. This work demonstrates multifunctional nanoparticles that efficiently inhibit tumors by PDT and reversing their immunosuppression to realize a versatile therapeutic strategy.