作者
Chunwei Tang,Weiqiang Jing,Kun Han,Zhenmei Yang,Shengchang Zhang,M. Liu,Jing Zhang,Xiaotian Zhao,Ying Li,Chongdeng Shi,Qihao Chai,Z Li,Maosen Han,Yan Wei,Zhipeng Fu,Zhenlin Zheng,Kun Zhao,Ping Sun,Danqing Zhu,Chen Chen,Daizhou Zhang,Cuihong Li,Shilei Ni,Tao Li,Jiwei Cui,Xinyi Jiang
摘要
Sepsis, which is the most severe clinical manifestation of acute infection and has a mortality rate higher than that of cancer, represents a significant global public health burden. Persistent methicillin-resistant Staphylococcus aureus (MRSA) infection and further host immune paralysis are the leading causes of sepsis-associated death, but limited clinical interventions that target sepsis have failed to effectively restore immune homeostasis to enable complete eradication of MRSA. To restimulate anti-MRSA innate immunity, we developed CRV peptide-modified lipid nanoparticles (CRV/LNP-RNAs) for transient in situ programming of macrophages (MΦs). The CRV/LNP-RNAs enabled the delivery of MRSA-targeted chimeric antigen receptor (CAR) mRNA (SasA-CAR mRNA) and CASP11 (a key MRSA intracellular evasion target) siRNA to MΦs in situ, yielding CAR-MΦs with boosted bactericidal potency. Specifically, our results demonstrated that the engineered MΦs could efficiently phagocytose and digest MRSA intracellularly, preventing immune evasion by the "superbug" MRSA. Our findings highlight the potential of nanoparticle-enabled in vivo generation of CAR-MΦs as a therapeutic platform for multidrug-resistant (MDR) bacterial infections and should be confirmed in clinical trials.