Tailoring biomimetic dual-redox-responsive nanoplexes for enhanced RNAi-synergized photodynamic cancer immunotherapy.

Despite the strong potential of RNA interference (RNAi) therapies, critical issues, such as poor permeability across biological membranes and efficacy of their delivery into the cytoplasm, remain to be addressed before their successful clinical application. The current study aimed to address these issues by constructing a biomimetic nanoplex with dual redox responsiveness, which is derived from a cationic polymer formed by the condensation of endogenous spermine monomers via diselenide bonds. The developed nanoplexes decomposed in response to the redox microenvironment in cancer cells, thereby avoiding accumulation toxicity and poor transfection efficiency owing to incomplete siRNA release. When co-delivered with siPDL1 and a photosensitizer, the reactive oxygen species generated by irradiated nanoplexes accelerated the cytoplasmic release of siPDL1, which was expected to alleviate the PDT-induced increase in immunosuppressive PD-L1 expression. In a murine model of 4T1 xenografted breast cancer, the fabricated macrophage membrane (MPM)-camouflaged nanoplexes with payloads boosted antitumor immune responses in situ through a "self-synergistic" immunogenic cell death induced by photodynamic therapy (PDT). Overall, the study reported a new strategy for harnessing photodynamic immunotherapy for treating immunologically cold tumors. STATEMENT OF SIGNIFICANCE: This study provides a biomimetic nanoplex with dual redox responsiveness, which is derived from a novel cationic polymer formed by the condensation of endogenous spermine monomers through diselenide bonds. The developed nanoplex disassembles according to the redox microenvironment in cancer cells, thereby avoiding accumulation toxicity and poor transfection efficiency due to incomplete siRNA release. When co-delivery of siPDL1 and photosensitizer in vivo, the ROS generated by irradiated nanoplexes accelerated the cytoplasmic release of siPDL1, and which is expected to alleviate PDT-induced increase in immunosuppressive PD-L1 expression, thereby boosting antitumor immune responses in situ through a "self-synergistic" immunogenic cell death induced by PDT. Our findings reveal a new strategy of harnessing photodynamic immunotherapy therapy toward immunologically cold tumors.