MicroRNA-driven periodontal immune homeostasis and tissue regeneration: from regulatory networks to engineering translation.

Periodontitis is a chronic immune-inflammatory disease induced by dental plaque biofilms. Persistent host immune dysregulation disrupts the dynamic balance between local tissue repair and pathological destruction, ultimately leading to irreversible damage to the periodontal supporting tissues, including the alveolar bone, periodontal ligament, and cementum. As key post-transcriptional regulators, microRNAs (miRNAs) coordinate the osteogenesis-bone resorption balance, immune homeostasis, angiogenesis, and intercellular communication through multi-target synergistic mechanisms, and have thus emerged as promising intervention targets for restoring periodontal immune homeostasis and achieving tissue regeneration. However, existing studies predominantly follow a simplified "single miRNA-single target-single phenotype" paradigm, and the three stages-molecular mechanism elucidation, delivery vector construction, and clinical validation-remain disconnected from one another. Published reviews likewise lack a comprehensive analytical framework that integrates multi-level miRNA regulatory networks with engineered delivery strategies. This review first systematically elucidates how endogenous microenvironmental factors, exogenous interventions, and mechanical stimuli regulate miRNA expression in periodontal tissues. It then examines the core functions of miRNAs across three dimensions-osteogenic/osteoclastic differentiation, immune homeostasis, and angiogenesis-analyzes their molecular interactions with competing endogenous RNAs (ceRNAs), summarizes the intercellular communication functions of miRNAs mediated by extracellular vesicles (EVs), and provides a graded synthesis of the research evidence for core miRNAs. At the translational engineering level, this review comprehensively surveys five strategies: miRNA mimic delivery, miRNA inhibition and blockade, indirect regulation of endogenous expression, engineered EV delivery, and DNA nanorobots. On this basis, it identifies three core bottlenecks constraining the field-the complexity of molecular regulatory networks, insufficient adaptability of delivery systems, and an incomplete preclinical validation framework-and proposes a spatiotemporally coordinated model for periodontal regeneration based on three sequential stages of intervention: "inflammation regulation, osteogenic-vascular coupling, and tissue maturation and remodeling." This review aims to overcome the fragmentation of previous research by providing a systematic framework for elucidating the immune regulatory mechanisms of miRNA-mediated periodontal regeneration, developing smart responsive scaffolds, and conducting preclinical validation in large animals, while advancing the clinical translation of miRNA-based multi-target regulatory strategies in periodontal regeneration.