Exosomal microRNAs in Periodontitis: From Molecular Footprints to Clinical Frontiers

Periodontitis is a widespread chronic inflammatory disease driven by host–microbial interactions and immune dysregulation, often resulting in alveolar bone loss and systemic complications. Exosomes, small extracellular vesicles enriched with microRNAs (miRNAs), have emerged as central modulators of these processes, mediated intercellular communication, and influenced inflammation, immunity, tissue homeostasis, and host–pathogen interactions in the periodontal microenvironment. Existing literature has identified their diagnostic relevance; however, a comprehensive framework connecting molecular mechanisms to clinical applications remains lacking. This narrative review proposes an integrative conceptual framework that illustrates the progression from exosomal miRNA biogenesis to their regulatory roles in periodontal disease, linking microbial triggers, immune modulation, and their emerging clinical relevance. We trace the molecular footprints of these exosomal miRNAs, particularly miR-146a, miR-155, and miR-223, and assess their dynamic roles as both biomarkers and regulatory agents in inflammation and tissue remodeling. Recent analytical advances, including systems biology, multiomics integration, and network modeling, are examined for their potential to decode complex miRNA-mediated pathways. Integration of transcriptomic, proteomic, and exosomal data is highlighted as a promising approach to enhance mechanistic insights and predictive accuracy. We also evaluate emerging diagnostic and therapeutic applications of exosomal miRNAs, particularly their potential in noninvasive biomarker development and targeted regenerative strategies. Key translational challenges are addressed, including the lack of standardized isolation protocols, interindividual biological variability, and the need for in vivo validation. Future directions should prioritize the development of engineered exosomes for targeted miRNA and anti-inflammatory delivery, alongside exosomal miRNA-based biosensors for real-time, minimally invasive disease monitoring. By bridging molecular footprints with emerging analytical approaches, this review offers a forward-looking perspective on the translational potential of exosomal miRNAs in periodontology, demonstrating their potential in advancing precision diagnostics and targeted therapeutics.