Targeted biomimetic fusogenic liposome enhances tumor accumulation, penetration, and therapeutic efficacy of siRNA therapeutics

Blocking the CD47-SIRPα signaling pathway to promote macrophage phagocytosis represents a promising strategy for cancer therapy. RNA interference offers a safe and efficient means to disrupt this pathway, highlighting the importance of developing effective siRNA delivery systems to improve antitumor efficacy. In this study, we developed a biomimetic and fusogenic liposome capable of deep tumor penetration and selective tumor cell targeting for the coordinated cytosolic delivery of CD47 and PLK1-targeting siRNAs. CD47 siRNA downregulated CD47 protein expression, suppressing the "don't eat me" signal, while PLK1 siRNA induced tumor cell apoptosis and enhanced the "eat-me" signal by facilitating the translocation of calreticulin to the cell surface. This biomimetic platform enabled efficient tumor cell specific cytosolic delivery and deep tissue penetration of siRNAs. The combined silencing strategy significantly enhanced macrophage-mediated phagocytosis of tumor cells and improved antitumor outcomes in a 4T1 tumor-bearing mouse model. Overall, this study presents a biomimetic fusogenic liposomal system that amplifies macrophage phagocytosis and suppresses tumor growth, providing a promising therapeutic avenue for triple-negative breast cancer.