Antimicrobial peptide-derived lipid nanoparticles enable lung-targeted mRNA therapy for multidrug-resistant bacterial pneumonia

  • J Control Release. 2026 May 23:396:115047. doi: 10.1016/j.jconrel.2026.115047.
Xucheng Hou  1 ,  Shi Du  2 ,  Wenxi Zhang  3 ,  Wenkai Zhou  4 ,  Rui Mao  4 ,  Chang Wang  5 ,  Guanghua Peng  3 ,  Yansha Meng  3 ,  Mengya Yin  3 ,  Xinru Li  6 ,  Guiling Li  7
Affiliations
  • 1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China; Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, Singapore, Singapore. Electronic address: [email protected].
  • 2. International College of Pharmaceutical Innovation, Soochow University, Suzhou 215222, PR China.
  • 3. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug System; School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
  • 4. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.
  • 5. Stephenson School of Biomedical Engineering, The University of Oklahoma, Norman, OK 73019, USA.
  • 6. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug System; School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China. Electronic address: [email protected].
  • 7. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China. Electronic address: [email protected].
PMID: 42178062 DOI: 10.1016/j.jconrel.2026.115047
Abstract

Multidrug-resistant (MDR) Bacterial pneumonia presents a critical and growing clinical challenge, necessitating new therapeutic strategies. Here, we report an antimicrobial peptide-derived lipid nanoparticle system for lung-targeted delivery of mRNA encoding cathelicidin, a secreted host defense peptide with broad antimicrobial activity. This design enables the coordinated killing of both intracellular and extracellular bacteria, addressing a barrier in treating Bacterial infections. A single systemic administration achieves robust pulmonary accumulation, leading to reduced Bacterial burden, suppressed inflammatory cytokines, and improved clinical outcomes and survival in mice with MDR Bacterial pneumonia. Together, this platform offers a novel strategy for treating MDR Bacterial pneumonia and may provide a generalizable framework for developing mRNA-based antimicrobials against recalcitrant respiratory infections.

Keywords
Antimicrobial peptide-derived lipid nanoparticles; Lipid nanoparticles; Multidrug-resistant bacteria; Pneumonia; mRNA delivery; mRNA therapeutics.
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