MicroRNAs in periodontal disease: from pathogenic mechanisms and RANKL/OPG regulation to nanoparticle delivery and personalized medicine.

Dysregulated host-microbe interactions are a hallmark of periodontal disease (PD), a chronic inflammatory condition that causes progressive alveolar bone resorption and tooth loss. MicroRNAs (miRNAs) have become important epigenetic regulators, offering new ways to understand disease pathophysiology and to provide tailored treatments. The current analysis uniquely synthesizes pathogen-specific miRNA signatures, modulation of the Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL)/Osteoprotegerin (OPG) axis, periodontal ligament stem cells (PDLSCs) osteogenesis, and enhanced delivery platforms into a coherent precision medicine framework, in contrast to other studies that examined these areas independently. We investigate the role of miRNAs in PD, assess their potential as non-invasive diagnostic biomarkers, and review novel therapeutic approaches targeting these molecules. Porphyromonas gingivalis and other periodontal infections cause aberrant miRNA expression that accelerates bone loss by impairing the development of PDLSCs, disrupting the RANKL/OPG axis, and sustaining pro-inflammatory cytokine cascades (IL-1, IL-6, TNF-α). Based on replication across many independent investigations, three of the many identified miRNAs-miR-146a, miR-155, and miR-223-show the most promise for diagnosis and treatment. These miRNAs, found in saliva and gingival crevicular fluid, serve as reliable non-invasive indicators. Preclinical studies show that anti-miR inhibitors and miRNA mimics, administered via hydrogels or nanoparticles, successfully reduce inflammation and promote alveolar bone repair. However, several issues remain unresolved, including miRNA instability, off-target effects, and interpatient variability, as well as contradictory results from multiple studies, such as the opposing functions of miR-21 across various cell types. In summary, targeted host modification by miRNA-based therapies is a paradigm change from traditional symptomatic therapy. To incorporate these strategies into clinical practice and eventually enable regenerative and customized periodontal treatment, it will be crucial to address current delivery and safety constraints through improved nanocarriers and patient-specific profiling.