A Comprehensive Review of Antimicrobial Peptides and Smart Biomaterials in Chronic Wound Therapy: Overcoming Biofilms, Resistance, and Translational Barriers

Chronic wounds represent a growing global healthcare burden driven by persistent inflammation, polymicrobial biofilm formation, impaired tissue regeneration, and increased antimicrobial resistance. This review examines the mechanistic interplay between chronic wound pathophysiology, biofilm persistence, and antimicrobial peptide (AMP)-based therapeutics, with particular emphasis on translational barriers and advanced biomaterial-enabled delivery strategies. Current evidence demonstrates that AMPs exert multifactorial activities extending beyond direct antimicrobial effects, including membrane disruption, quorum-sensing inhibition, extracellular polymeric substance (EPS) destabilization, immune modulation, angiogenic stimulation, and promotion of re-epithelialization. However, their clinical translation remains limited due to proteolytic degradation, poor stability, cytotoxicity, rapid clearance, and inadequate retention within the hostile chronic wound microenvironment. To address these limitations, emerging biomaterial platforms—including hydrogels, electrospun nanofibers, nanoparticles, self-assembling peptide systems, and stimuli-responsive smart dressings—have been developed to improve AMP stability, controlled release, biofilm penetration, and regenerative efficacy. This review further highlights current preclinical and clinical challenges, including the lack of standardized polymicrobial biofilm models and translationally relevant wound systems, while discussing future perspectives such as artificial intelligence-assisted peptide design and precision wound therapeutics. We argue that peptide discovery is no longer the principal bottleneck: the rate-limiting steps are now peptide stabilization, biofilm-targeted delivery, and dosing, and no current platform yet couples validated eradication of mature polymicrobial biofilms with validated tissue regeneration in a clinically representative model. Collectively, AMP-enabled smart biomaterials may support the transition from passive wound management toward responsive, biofilm-targeted regenerative therapy.