Abstract
INTRODUCTION: Peri‐implantitis, characterized by inflammatory bone loss, is a leading cause of dental implant failure. Current regenerative strategies face limitations due to the persistent inflammatory microenvironment. Mesenchymal stem cell‐derived extracellular vesicles (MSC‐EVs) have emerged as promising acellular therapeutics with dual osteogenic and immunomodulatory capacities, offering a novel approach to address the complexity of peri‐implant bone defects. METHODS: This narrative review synthesizes preclinical evidence on MSC‐EVs for peri‐implant bone regeneration. It examines methods for EV isolation from various sources. Furthermore, it analyzes advanced engineered delivery systems, such as peptide‐functionalized implant surfaces and bioactive scaffolds, designed to enhance local retention and therapeutic efficacy. RESULTS: MSC‐EVs orchestrate bone regeneration through multifaceted mechanisms. They directly stimulate osteogenesis by transferring pro‐osteogenic miRNAs and proteins, activating key pathways like PI3K/AKT and Wnt/β‐catenin. Crucially, they modulate the osteoimmune environment by reprogramming macrophages toward a reparative M2 phenotype, suppressing pro‐inflammatory Th1/Th17 responses, and expanding regulatory T cells (Tregs). Concurrently, MSC‐EVs inhibit bone resorption by favorably modulating the RANKL/OPG balance and directly interfering with osteoclast differentiation. They also promote neovascularization, a critical factor for healing in ischemic zones. Preclinical models demonstrate that localized delivery via engineered systems significantly enhances osseointegration, bone‐implant contact, and regeneration of functional bone‐vessel units. CONCLUSION: MSC‐EVs represent a promising and multifaceted therapeutic strategy for bone regeneration in peri‐implantitis, simultaneously targeting inflammation, bone resorption, and osteogenesis. While robust preclinical evidence supports their role in halting bone loss and promoting structured regeneration, successful clinical translation requires further standardization, optimization of delivery, and validation in human trials.