Engineered extracellular vesicles as multifunctional therapeutics for restoring periodontal homeostasis

Periodontal homeostasis refers to the dynamic equilibrium between host defense, microbial control, and tissue remodeling in periodontal tissues. Periodontitis is a chronic inflammatory disease characterized by the destruction of periodontal tissues, in which periodontal homeostasis is disturbed. Although many strategies have been developed, treatment of periodontitis and restoration of periodontal homeostasis remain challenging. Extracellular vesicles (EVs) have emerged as a potential cell-free platform for therapeutic applications due to their intrinsic capacity for intercellular communication and biocompatibility. With the advances in engineering, EVs can be functionally tailored to exhibit improved stability, targeting, and bioactivity, attracting increasing attention as regulators for periodontal homeostasis. Accumulating evidence indicates that engineered EVs exert diverse regulatory effects in the periodontal microenvironment, including anti-bacterial activity, anti-inflammatory properties, immunomodulation, antioxidant protection, regulation of programmed cell fate, and promotion of regeneration. Such multifunctional properties enable engineered EVs to address periodontal dysregulation and contribute to the stabilization of tissue homeostasis. This review highlights recent advances in the application of engineered EVs in periodontal research, summarizes their emerging therapeutic roles across these biological domains, and emphasizes their potential as versatile modulators for the maintenance and restoration of periodontal homeostasis. STATEMENT OF SIGNIFICANCE: This review uniquely integrates recent progress in engineering extracellular vesicles (EVs) with biomaterial-based strategies to restore periodontal homeostasis, a perspective not comprehensively addressed in existing literature. By systematically analyzing approaches such as cargo and surface modification, scaffold incorporation, and artificial vesicle design, it highlights how engineered EVs overcome the limitations of native vesicles and achieve multifunctional regulation of microbial, immune, and regenerative processes. This work provides insights into the convergence of materials science, nanotechnology, and oral biology, and outlines future directions for translating engineered EVs into next-generation therapeutic platforms with broad relevance for biomaterial innovation and regenerative medicine.