Local drug delivery systems for the periodontal microenvironment: from barrier penetration to multilevel synergy.

Periodontitis is a chronic inflammatory disease characterized by progressive destruction of periodontal supporting tissues. Although local drug delivery systems (LDDSs) enable site-specific therapy, their clinical efficacy remains limited by the dynamic and heterogeneous periodontal microenvironment. This review systematically delineates multiscale barriers to effective delivery, including biofilm resistance, gingival crevicular fluid (GCF)-mediated clearance, immune-mediated degradation, and impaired tissue regeneration. In response, LDDS design has evolved from passive carriers to multilevel synergistic systems, integrating responsiveness to multiple stimuli and programmed release that aligns with the antibacterial-anti-inflammatory-regenerative sequence. The emergence of theranostic platforms further enables real-time monitoring and feedback-controlled intervention. Despite these advances, a significant translational gap persists. Current models fail to recapitulate the polymicrobial and chronic nature of periodontitis, while overlooked in vivo phenomena, including protein corona formation and the reactive oxygen species (ROS) paradox, may compromise therapeutic outcomes. Future strategies should prioritize physiological relevance and precise spatiotemporal regulation to facilitate clinical translation of LDDSs.