Self-Assembling Lauroylated Antimicrobial Peptide with Superior Antimicrobial Activity, Stability, and Selectivity

Antimicrobial peptides (AMPs) represent a promising strategy for combating antibiotic-resistant bacterial infections; however, their therapeutic application remains limited by high toxicity and poor stability. In this study, we designed a class of core-shell nanoparticles through the self-assembly of an imperfectly amphipathic peptide, with fatty acids of varying chain lengths acting as stabilizing agents. The lead nanoparticle, designated GV2, demonstrated superior antibacterial efficacy, safety, and stability compared to its nonassembled peptide form. GV2 exhibited a rapid bactericidal effect and potent activity against both planktonic and biofilm-associated bacteria, with no observed development of bacterial resistance. Mechanistic investigations revealed that GV2 permeabilized and ruptured bacterial membranes by targeting three major components in the bacterial membrane including lipopolysaccharide (LPS), lipoteichoic acid (LTA), and phosphatidylglycerol (PG). Notably, GV2 effectively protected against skin wound infections in a therapeutic context, highlighting its clinical potential. This study not only presents a promising antimicrobial candidate but also provides a strategic framework for the rational design of stable and safe AMPs.