Overcoming Oral Environmental Barriers: Nanoengineering Strategies for Antimicrobial Peptides in Biofilm-Associated Oral Diseases

Abstract Biofilm-associated oral diseases impose a substantial global health burden and are closely linked to systemic inflammation. Although antimicrobial peptides (AMPs) offer a promising alternative to conventional antibiotics, their therapeutic efficacy in the oral cavity is limited by barriers in the oral environment. Free AMPs are rapidly removed by salivary flow, destabilized by local proteases, and impeded by substantial diffusion barriers within mature biofilms. Nanoengineering provides a systematic approach to address these limitations. In this review, we present a barrier-oriented framework for AMP delivery and examine how nanomaterial design addresses the specific constraints of the oral environment. Interfacial engineering prolongs local retention, spatial protection preserves AMP stability, and microenvironment-responsive systems provide on-demand activation for effective biofilm disruption. Alongside these approaches, multifunctional nanosystems combining antimicrobial, immunomodulatory, and regenerative activities are discussed. Finally, key translational challenges, including biosafety, microbiome homeostasis, manufacturing, and regulatory barriers, are critically examined. This review traces the development of AMP nanoengineering from passive delivery vehicles toward precision therapeutic platforms that respond dynamically to the oral microenvironment.