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

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.