Optimization strategies for antimicrobial peptides in dental caries prevention and management: from emerging mechanisms of action to clinical translation.

Dental caries remains a prevalent global health burden driven by dysbiosis of the biofilm microbiome. Antimicrobial peptides (AMPs), characterized by a low risk of resistance development and immunomodulatory potential, have emerged as promising alternatives to conventional antimicrobials; however, their clinical translation is still constrained by physiological instability, cytotoxicity, limited oral substantivity, and substantial regulatory and economic barriers. This review systematically summarizes recent advances in the mechanisms of action, rational design, and translational strategies of AMPs for the prevention and management of dental caries. The article first outlines updated mechanistic concepts, highlighting a shift from the classical stable pore-forming model toward transient water channel formation and lipid flip-flop models, and further discusses microbiome-oriented ecological modulation strategies aimed at preserving beneficial commensals and suppressing cariogenic dysbiosis. In addition, structure-activity relationships are examined in depth, with emphasis on how diverse optimization approaches can balance peptide activity, toxicity, stability, selectivity, and manufacturability. The review also delineates the major barriers that impede clinical translation, including production cost, GMP-compatible manufacturing, batch consistency, delivery format, and regulatory definability. Potential strategies are discussed, including molecular farming in plant bioreactors, recombinant or synthetic production platforms, covalent immobilization,