Precision-engineered polymer topologies: balancing potent antibacterial efficacy with enhanced biocompatibility

The escalating threat of antimicrobial resistance demands the development of innovative therapeutic strategies. Host-defense peptides (HDPs) and their synthetic mimics exhibit broad-spectrum antibacterial activity, yet their clinical translation is frequently hindered by cytotoxicity arising from nonspecific interactions with mammalian cell membranes. Recent advances in polymer science, particularly controlled polymerization techniques, have enabled the precise synthesis of well-defined antibacterial polymers and systematic evaluation of structure-activity relationships. This review provides a comprehensive overview of the development and fundamental mechanisms of antibiotic resistance and highlights the evolution of antibacterial polymers from HDP-inspired molecular designs toward precise biofunction control. Key advances in optimizing structural determinants governing antibacterial activity and biocompatibility are discussed, with particular emphasis on compositional parameters and polymer topology, including linear, cyclic, hyperbranched, star, and bottle brush architectures. In addition, emerging approaches based on stimuli-responsive and self-immolative polymers that enable on-demand degradation are presented as effective means to reduce long-term cytotoxicity and environmental accumulation. Concurrently, increasing attention has been directed toward non-amphiphilic polymer systems, which expand the current design landscape by offering alternative pathways to antibacterial activity beyond conventional amphiphilic design principles. Finally, future perspectives involving synergistic and combination therapies, together with data-driven and AI-assisted approaches for pathogen-specific polymer design, are outlined as promising routes to improve selectivity while maintaining or even enhancing antimicrobial efficacy.