A pH-ultrasensitive membranolytic polymer-assisted delivery system for enhanced siRNA delivery

Endosomal escape is a limiting factor for the in vivo application of nucleic acid therapeutics and remains a major challenge in the development of drug delivery systems. In this study, we developed a pH-ultrasensitive membranolytic polymer (P(C6-Bn_X))-assisted delivery system (NP_BnX) to facilitate siRNA endosomal escape and enhance the gene silencing efficiency. The incorporation of P(C6-Bn_X) imparts the siRNA delivery system with enhanced cellular uptake, effective membranolytic activity under endosomal pH conditions, and improved endosomal escape efficiency of siRNA. The significantly enhanced siRNA-mediated gene silencing efficacy was also confirmed in multiple tumor cell lines. Further investigations demonstrated that the delivery of siRNA targeting CD47 via this system effectively suppressed the expression of CD47 at both the cellular level and in vivo, thereby enhancing macrophage-mediated phagocytosis of tumor cells and promoting anti-tumor immune responses. This study provides a promising and viable strategy for the design and development of siRNA delivery systems.