AI and Nanodelivery Systems Enhance Host-Defense Peptides to Combat Biofilms and Antimicrobial Resistance

The escalating crisis of antimicrobial resistance (AMR), coupled with the pervasive formation of bacterial biofilms and persister cells, renders conventional antibiotics increasingly ineffective. These complex microbial structures shield bacteria from immune responses and drug penetration, leading to persistent and difficult-to-treat infections. Host-defense peptides (HDPs), also known as antimicrobial peptides (AMPs), represent a promising alternative due to their broad-spectrum activity and diverse mechanisms, often circumventing typical resistance pathways. However, their clinical utility is hampered by issues like poor stability, rapid degradation, and non-specific toxicity, necessitating innovative strategies for optimization.

This comprehensive review critically evaluated the current landscape of host-defense peptides (AMPs) and strategies to overcome their limitations in treating antimicrobial resistance (AMR) and biofilm-associated infections. Researchers analyzed rational design approaches for next-generation AMP discovery, highlighting optimization techniques such as sequence engineering and chemical modification. The review also discussed the synergistic potential of combining AMPs with existing antibiotics or adjuvants. A significant focus was placed on nanoscale delivery platforms, examining their role in enhancing AMP stability, facilitating targeted delivery to infection sites, and improving penetration through dense biofilm matrices. Key chemical properties, delivery kinetics, and stimuli-responsive drug delivery systems were also explored.

The review found that integrating advanced strategies significantly enhances the efficacy of host-defense peptides (AMPs) against antimicrobial resistance (AMR) and biofilms. Artificial intelligence (AI)-assisted designs, alongside sequence engineering and chemical modifications, were identified as crucial for improving AMP antibacterial activity, stability, and biocompatibility. Nanoscale delivery platforms, including both organic- and inorganic-based systems, were shown to overcome key challenges by providing enhanced stability, enabling targeted delivery, and facilitating superior biofilm penetration. These platforms also offer the potential for stimuli-responsive drug release, optimizing antibacterial and antibiofilm actions.

Synergistic combinations of AMPs with conventional antibiotics or adjuvants were highlighted as a potent strategy to amplify therapeutic effects and mitigate resistance development. The review underscored that diverse modification techniques are essential to develop innovative AMPs with improved safety profiles and significant antibacterial activity for future AMR therapy, addressing current research gaps and clinical obstacles.