Xuanbo Zhang, Shipeng Ning, Feng Fang, Cao Zhou, Zifan Yang, Liping Cao, Kaiyuan Wang, Zunyong Feng, Bingyu Li, Dixian Luo, Xiao Xu, Zhigang Liu, Xiaoyuan Chen, Zhiqiang Yu
Cisplatin's clinical utility is limited by its toxicity, drug resistance, and promotion of immune suppression due to phosphatidylserine (PS) exposure during tumor cell apoptosis. This study introduces a novel approach that integrates cisplatin-derived lipid prodrugs into lipid nanoparticles (PtLNPs) to overcome these challenges. By converting cisplatin to lipid derivatives, we facilitate its incorporation into LNPs, enhancing both the delivery and protection of functional siRNA/mRNA molecules. The synthesized lipid-Pt prodrugs significantly improved the in vitro delivery efficiency and stability of these nucleic acids. Additionally, a codelivery system combining Xkr8 siRNA and annexin A5 (ANX5) mRNA within PtLNPs effectively mitigated cisplatin-induced PS exposure by inhibiting Xkr8 upregulation and promoting ANX5 expression to bind PS. In vivo studies demonstrated that the PtLNP system substantially enhanced the efficacy of combined chemotherapy and immunotherapy, offering a promising strategy to refine cisplatin-based cancer therapy by integrating nucleic acid delivery technologies.