Engineering host‑defense peptides enhanced by artificial intelligence and nano delivery systems to overcome biofilms and antimicrobial resistance

• We discuss rational design and AI-guided strategies shaping next-gen AMP discovery. • We highlight nano-delivery tactics improving AMP stability, targeting, and biofilm control. • We critically reviewed synergistic AMP approaches enhancing efficacy and biocompatibility. • Clinical gaps, obstacles, and prospects for AMPs in advancing AMR therapies are also discussed . Infections caused by bacteria pose a risk to humanity as drugs become increasingly ineffective as resistance to bacterial strains emerge along with biofilm and persister formation. This review critically evaluates host defense peptides, rational design strategies that have guided next-generation antimicrobial peptide (AMP) discovery, and their current limitations. We also highlight optimization approaches including sequence engineering and chemical modification, synergistic combinations of antibiotics or adjuvants, and nanoscale delivery platforms that enhance stability, targeted delivery, and biofilm penetration. We also discuss the key chemical properties, delivery kinetics, and stimuli-responsive drug delivery for antibacterial and antibiofilm actions as well as the toxic effects of organic- and inorganic-based AMP delivery platforms. This underlines the importance of diverse modification techniques and artificial intelligence (AI)-assisted designs to improve the antibacterial activity, stability, and biocompatibility of AMPs. This study examines the latest advances in the combination of AMPs with drug delivery systems to improve clinical outcomes. Finally, the review discusses the clinical status, research gaps, current obstacles, and prospects of AMPs in antimicrobial resistance (AMR) therapy, offering key findings for the development of innovative AMPs with significant antibacterial activity, stability, and safety for AMR treatment.. .