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  3. mRNA-Laden Lipid-Nanoparticle-Enabled in Situ CAR-Macrophage Engineering for the Eradication of Multidrug-Resistant Bacteria in a Sepsis Mouse Model

mRNA-Laden Lipid-Nanoparticle-Enabled in Situ CAR-Macrophage Engineering for the Eradication of Multidrug-Resistant Bacteria in a Sepsis Mouse Model

  • ACS Nano. 2024 Jan 23;18(3):2261-2278. doi: 10.1021/acsnano.3c10109.
Chunwei Tang 1,  Weiqiang Jing 2,  Kun Han 1,  Zhenmei Yang 1,  Shengchang Zhang 1,  Miaoyan Liu 1,  Jing Zhang 1,  Xiaotian Zhao 1,  Ying Liu 1,  Chongdeng Shi 1,  Qihao Chai 1,  Ziyang Li 1,  Maosen Han 1,  Yan Wang 1,  Zhipeng Fu 1,  Zuolin Zheng 1,  Kun Zhao 1,  Peng Sun 3,  Danqing Zhu 4,  Chen Chen 5,  Daizhou Zhang 6,  Dawei Li 6,  Shilei Ni 7,  Tao Li 8,  Jiwei Cui 9,  Xinyi Jiang 1
Affiliations

Affiliations

  • 1 NMPA Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Cultural West Road, Jinan, Shandong Province 250012, China.
  • 2 Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Cultural West Road, Jinan, Shandong Province 250012, China.
  • 3 Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China.
  • 4 Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, 4572A Academic Building, Clear Water Bay, Kowloon, Hong Kong 999077, China.
  • 5 Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, Shandong Province 250012, China.
  • 6 Shandong Academy of Pharmaceutical Sciences, Jinan, Shandong Province 250101, China.
  • 7 Department of Neurosurgery, Qilu Hospital and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, 107 Cultural West Road, Jinan, Shandong Province 250012, China.
  • 8 Department of General Surgery, Qilu Hospital, Shandong University, 107 Cultural West Road, Jinan, Shandong Province 250012, China.
  • 9 Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, Shandong University, Jinan, Shandong Province 250100, China.
PMID: 38207332 DOI: 10.1021/acsnano.3c10109
Abstract

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.

Keywords

chimeric antigen receptor macrophage; immunosuppression; in situ engineering; lipid nanoparticle; methicillin-resistant Staphylococcus aureus; sepsis.

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