Lipidized LL37-loaded PLGA nanocarriers: Bioengineered peptide delivery systems for enhanced wound healing

Antimicrobial peptides (AMPs) such as LL37 offer a promising alternative to conventional antibiotics in treating chronic and multidrug-resistant wound infections. However, their clinical translation is limited by rapid degradation and cytotoxicity at high concentrations. This study investigates the encapsulation of a palmitoylated LL37 in a FDA-approved poly(lactic-co-glycolic acid) (PLGA) nanoparticles using two fabrication techniques, nanoprecipitation and microfluidics, to enhance stability and controlled peptide release. Microfluidic-generated nanoparticles demonstrated superior size uniformity, smaller hydrodynamic size (102.3 ± 2.0 nm vs 189.3 ± 3.4 nm), improved stability, and prolonged LL37(P) release compared to nanoparticles obtained via bulk nanoprecipitation method. LL37-encapsulated nanoparticles demonstrated controlled peptide release, enhanced keratinocyte uptake, and significant fibroblast-mediated wound closure acceleration. Proteomic analysis of the nanoparticle-protein corona revealed enrichment in proteins involved in coagulation, inflammation modulation, and extracellular matrix remodelling, suggesting an active role of nanoparticles in modulating the wound healing microenvironment. These findings highlight PLGA-based LL37 loaded nanocarriers as a promising biopolymer platform for AMP delivery in wound healing applications and as a viable therapeutic strategy in regenerative medicine and infection control.