Plant-derived peptide-polymer therapeutics emerge as potent solutions for cutaneous infections and inflammation, overcoming stability and delivery challenges.

Cutaneous infections and chronic inflammatory wounds are notoriously difficult to treat due to rising antimicrobial resistance, polymicrobial biofilms, and excessive protease activity. Current topical therapies often fall short, failing to penetrate the stratum corneum effectively or maintain sufficient local concentrations. Plant-derived antimicrobial peptides (AMPs) represent a compelling alternative, offering broad-spectrum antimicrobial, antibiofilm, immunomodulatory, and tissue-reparative properties. However, their inherent proteolytic instability and poor skin penetration severely limit clinical translation, creating a critical gap in effective topical treatments.

This comprehensive review critically evaluates the design principles, therapeutic mechanisms, and advanced delivery platforms for plant-based peptide-polymer therapeutics targeting cutaneous infection and inflammation. It summarizes major classes of plant-derived AMPs, including defensins, cyclotides, and thionins, alongside engineering strategies like self-assembly, PEGylation, and dendritic architectures. The authors discuss advanced delivery systems such as nanocarriers, liposomes, and electrospun fibers designed to improve peptide stability, local retention, and controlled release. Finally, the review identifies key translational bottlenecks, including selectivity, toxicity, scalability, and regulatory hurdles.

The review highlights that plant-derived AMPs, such as defensins and cyclotides, possess inherent antimicrobial, antibiofilm, and immunomodulatory activities, making them ideal candidates for cutaneous infection and inflammation management. A critical finding is that polymer engineering strategies, including self-assembly, PEGylation, and dendritic architectures, are essential to overcome the peptides' proteolytic instability and improve skin penetration. These modifications are crucial for enhancing the therapeutic window. > Advanced delivery platforms like nanocarriers, liposomes, and electrospun fibers significantly enhance peptide stability, prolong cutaneous residence time, and enable controlled release, addressing major limitations of free peptides and improving local bioavailability. However, the review also identifies substantial translational bottlenecks, including ensuring peptide selectivity to minimize cytotoxicity, achieving scalable and reproducible manufacturing, and navigating complex regulatory classifications. Insufficient clinical validation remains a significant barrier to bringing these promising therapeutics to market. The integration of mechanism-driven peptide optimization with quality-by-design manufacturing is emphasized for future development.