Saponin-mediated cell membrane interference nanomedicine potentiates tumor chemo-immunotherapy via perforin-granzyme-like mechanism

Pore formation can facilitate the release of various intracellular substances upon cell death, which is of critical benefit in tumor immunotherapy by immunogenic cell death (ICD). Given that effective endogenous antigen release is of primary importance for ICD-eliciting immunogenicity, in addition to enhancing the cytotoxicity of ICD, we designed an immunogenic induction strategy via pore formation based on saponin, a composite medium of membrane-disrupting agents. In this study, saponin/polyphenol (ZS-TA) at appropriate concentrations directly caused membrane perforation by removing cholesterol from the membrane, thereby leading to the release of intracellular substances. Simultaneously, in situ nano-antigens (nano-Ags) were formed through the mechanism of protein-polyphenol interaction, and the nano-Ag served as a reservoir of antigens to trigger long-term immune effects. Meanwhile, this membrane perforation enhanced the uptake of chemotherapeutic drugs, serving as a general approach for drug delivery. Therefore, this work provides insights into the design of enhanced drug delivery systems and in situ vaccines to sensitize tumor chemo-immunotherapy.