2. Academic Validation
  3. Functional lipid nanoparticles for safe delivery of macromolecular antibiotics to gram-negative bacteria

Functional lipid nanoparticles for safe delivery of macromolecular antibiotics to gram-negative bacteria

  • J Control Release. 2025 Aug 10:384:113907. doi: 10.1016/j.jconrel.2025.113907.
Melgious J Y Ang 1,  Nithiyaa Balakrishnan 1,  Ki Hyun Bae 1,  Qiangqiang Wang 2,  Zhengjie Wu 2,  Yanming Wang 1,  Pinzheng Zhang 3,  Brandon Y L Seow 1,  Xiaoli Liu 4,  Yi Yan Yang 5
Affiliations

Affiliations

  • 1 Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, Centros #06-01, Singapore 138668, Republic of Singapore.
  • 2 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Centre for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou City 310003, PR China.
  • 3 NUS Graduate School, Integrative Sciences and Engineering Programme, 21 Lower Kent Ridge Road, Singapore 119077, Republic of Singapore.
  • 4 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Centre for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou City 310003, PR China; College of Medicine, Zhejiang University, Hangzhou City 310058, PR China.
  • 5 Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, Centros #06-01, Singapore 138668, Republic of Singapore. Electronic address: yyyang@bti.a-star.edu.sg.
PMID: 40451556 DOI: 10.1016/j.jconrel.2025.113907
Abstract

Lipid nanoparticles (LNPs) hold great potential for delivery of macromolecular antimicrobials. Herein, we designed a series of anionic LNPs capable of delivering cationic polymyxin B (PMB) for effective and safe treatment of Gram-negative Bacterial infection. The use of anionic lipid induced self-assembly of PMB, encapsulating cationic PMB molecules into LNPs via electrostatic interactions (PMB-LNPs). Anionic lipid architecture and lipid:PMB mixing ratios had a substantial influence on particle size, surface charge, and drug release properties of PMB-LNPs. Following in vitro screening assays, C14-Glu5/PMB (1:4) LNP was identified as the lead formulation due to its potent bactericidal activity against a panel of tested Gram-negative bacteria strains. Confocal and SEM imaging studies validated the importance of fractionated PMB release in mediating the enhanced binding of C14-Glu5/PMB (1:4) LNPs on the Bacterial outer membrane. Additionally, PMB-LNPs conferred prolonged blood circulation, preferential liver accumulation, and superior tolerability over free PMB. In a murine neutropenic A. baumannii Infection model, administration of C14-Glu5/PMB LNPs eliminated bacteria in the liver and suppressed Bacterial regrowth in the kidney more effectively than free PMB, resulting in an improved body weight status and histological appearance. This study may provide insights into the de novo design of LNP-based nanomedicines for antimicrobial therapies.

Keywords

Bacteremia; Lipid nanoparticles; Membrane disruption; Oligoglutamate; Polymyxin.

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