Systematic Review: Porphyromonas gingivalis Outer Membrane Vesicles From Pathogenesis to Therapeutic Implications

Background: Outer membrane vesicles (OMVs) from Gram-negative bacteria are spherical lipid bilayer nanostructures with diameters of 20 to 250 nm. Porphyromonas gingivalis (P. gingivalis), a keystone periodontal pathogen, releases OMVs that mediate its virulence and systemic pathological effects. Methods: This systematic review followed PRISMA guidelines and included studies from PubMed, Scopus, and Web of Science up to 2025. Results: A total of 62 articles were incorporated into the analysis. Generally, OMVs of P. gingivalis play a role in mediating interbacterial communication and are involved in pathogen-host interactions. These processes contribute to periodontal tissue destruction and systemic dissemination via blood vessels, thereby being associated with multiple systemic diseases. Key findings are as follows: (1) Periodontal destruction: OMVs inhibit endothelial cells (ECs)-mediated osteogenesis via the cGAS-STING-TBK1 pathway and induce apoptosis in human periodontal ligament stem cells (hPDLSCs) through the msRNA45033-CBX5-p53 methylation axis. Moreover, OMVs induce ferroptosis in BMSCs via the Hippo-YAP pathway. (2) Oral squamous cell carcinoma (OSCC) progression: OMVs promote the development of OSCC by inducing NF-κB-regulated ferroptosis. Additionally, sRNA23392 within OMVs downregulates desmocollin-2, which impairs the invasion and migration of OSCC cells. (3) Systemic dissemination: OMVs can cross the blood-brain barrier (BBB) to transport bacterial components to distant organs, which is associated with Alzheimer's disease, cardiovascular disease, and diabetes mellitus. (4) Immune modulation: OMVs interact with macrophages and dendritic cells to trigger robust immune responses, inducing the secretion of pro-inflammatory cytokines. Conclusions: P. gingivalis OMVs act as key mediators of virulence dissemination and significantly modulate host-microbe interactions along the oral-systemic axis. This systematic review consolidates recent advancements in the research on P. gingivalis OMVs, emphasizing their roles in immunoregulation, pathogenic mechanisms, and associations with both periodontal and systemic diseases. Gaps in existing literature include strain-specific heterogeneity of OMVs and the dose-response relationships within systemic disease contexts. Future studies should employ multi-omics approaches and standardized methodologies to elucidate their heterogeneity and dose-response relationships, facilitating targeted therapies.