Topical strategies for antimicrobial delivery of peptide medicines for the management of chronic wounds

Abstract

Chronic wounds remain difficult to manage because persistent infection, biofilm formation, and antimicrobial resistance limit the effectiveness of conventional antibiotics. Antimicrobial peptides (AMPs) have emerged as promising therapeutic alternatives because they combine broad-spectrum membrane activity with quorum-sensing interference and immunomodulatory effects but generally impose a lower resistance burden than single-target antibiotics do. This review examines topical delivery systems designed to improve AMP stability, local bioavailability, targeted release, and residence time within the wound microenvironment. Hydrogels and films provide moist, biocompatible matrices for localized and sustained peptide release, including alginate-based systems with activity against Pseudomonas aeruginosa biofilms. Nanoparticle platforms, including lipid, metallic, liposomal, and micellar systems, can protect AMPs from enzymatic degradation and generate depot-like release profiles against drug-resistant pathogens such as methicillin-resistant Staphylococcus aureus. Biopolymer scaffolds, microneedles, and stimuli-responsive carriers activated by pH, reactive oxygen species, temperature, light, or ultrasound provide spatiotemporal control of AMP deployment in infected wounds. These strategies are particularly relevant to chronic diabetic wounds, where delayed healing, persistent inflammation, and biofilm burden frequently coexist. Smart design elements, including extracellular matrix-mimetic nanofibers, integrated pH and cytokine sensors, cyclic peptides, and dendrimers, further extend AMP function by linking antimicrobial activity with tissue regeneration and wound monitoring. Preclinical studies report accelerated closure, reduced inflammatory burden, and biofilm disruption, but clinical translation remains limited by manufacturing scalability, dose-dependent cytotoxicity, sterilization stability, and limited human validation. Overall, next-generation topical AMP delivery systems offer a rational route to combine infection control with regenerative wound repair while reducing the reliance on conventional antibiotics.