Abstract
Periodontitis is a prevalent and destructive inflammatory disease that is closely linked to various systemic conditions. In recent years, the local delivery of therapeutic agents via novel biomaterials has emerged as a promising strategy for periodontitis therapy. Notably, the pathological reduction of endogenous power of hydrogen (pH) within periodontal pockets provides a valuable trigger for stimuli-responsive drug delivery. This narrative review aims to summarize advances in endogenous pH-responsive drug delivery systems (DDS) for periodontitis treatment, with a focus on their design mechanisms and therapeutic potential. A comprehensive literature search was conducted in PubMed/Medline, Web of Science, Scopus, and Embase (up to March 2025) using keywords 'pH-responsive', 'drug delivery', and 'periodontitis'. Studies investigating the preparation and in vitro/in vivo therapeutic effects of pH-responsive DDS for periodontitis were included and critically evaluated. pH-responsive materials are capable of undergoing structural transformations and triggering drug release in the pathological acidic microenvironment of periodontitis. The DDS based on these materials can be broadly classified into three categories: nanoparticles, nanofibers, and hydrogels. The protonation and the cleavage of chemical bonds are the primary response mechanisms. Programmed periodontitis recovery is crucial in the design of these DDS. pH-responsive DDS offer a promising strategy for localized periodontal therapy. However, challenges such as clinical translation, biosafety evaluation, and personalized release modulation remain. Future research should focus on multifunctional, programmable platforms to accelerate clinical adoption.