Homologous-Targeting Porous Type I/II Nanophotosensitizers for Efficient Delivery of STING Agonists and Enhanced Photodynamic Cancer Immunotherapy

Immunotherapy as a transformative cancer treatment modality frequently struggles with the immunosuppressive tumor microenvironment, which hinders effective immune responses. In this report, we construct biomimetic tumor cell membrane-cloaked porous covalent organic framework (COF) nanophotosensitizers (CMSCOFs) to synergistically enhance photodynamic therapy (PDT) and stimulate interferon genes (STING)-mediated immunotherapy. CMSCOF is prepared from porphyrin and benzothiadiazole-based units and cloaked with 4T1 cancer cell membranes for homologous tumor targeting. The porous structure of COF enables efficient encapsulation of the non-nucleotide STING agonist SR717. Upon 660 nm light irradiation, CMSCOFs trigger both type I and II photodynamic effects by producing both superoxide (O₂^•-) and singlet oxygen (¹O₂). The tumor cell membrane-cloaked design improves the stability of the nanophotosensitizers and mimics the natural cancer cells for enhanced blood circulation, tumor accumulation, and homologous-targeting to tumors. Inside tumor tissues, this unique CMSCOF design leads to enhanced immunogenic cell death (ICD) of tumor cells upon exposure to light irradiation. Furthermore, the encapsulated STING agonist SR717 is released after cellular internalization to activate the STING pathway and elicit a potent antitumor immune response. This synergistic approach effectively reverses the immunosuppressive tumor microenvironment, enhances cytotoxic T cell infiltration, and suppresses both primary and metastatic tumors, demonstrating the potential of CMSCOF nanophotosensitizers as a promising platform for photodynamic cancer immunotherapy.