Natural Bioactive Agents as Adjunctive Candidates in Periodontitis: Mechanistic Links to Cardiovascular Disease and Translational Challenges

Periodontitis is a highly prevalent chronic inflammatory disease that destroys the tooth-supporting tissues and has been consistently associated, in observational studies, with low-grade systemic inflammation and atherosclerotic cardiovascular disease, although whether this reflects a direct contribution to vascular disease, shared risk factors, or both remains unresolved. Subgingival instrumentation is the standard of care. Natural bioactive agents have been investigated as adjuncts because selected formulations exhibit antimicrobial, anti-inflammatory, antioxidant, pro-resolving, or reparative actions. This critical narrative review analyzes mechanistic, preclinical, and clinical evidence and asks whether effects on pathways shared by periodontal and vascular biology constitute a plausible, but unproven, link to cardiovascular health. Clinical trials have reported small, short-term changes in periodontal surrogate outcomes for selected formulations. They do not establish non-inferiority or equivalence to chlorhexidine, and none assessed cardiovascular events. Local gels, nanoparticles, and adhesive local formulations are being developed to address the poor bioavailability limiting several agents, though clinical validation remains preliminary. Formulations may improve periodontal exposure, but they add a second experimental variable and remain incompletely validated in humans. Systemically administered omega-3 fatty acids, melatonin, vitamin D, and polyphenols also require separate consideration because direct extra-periodontal effects and drug interactions can occur independently of periodontal change. Natural bioactive agents should therefore be regarded as investigational adjuncts rather than replacements for mechanical therapy. Their cardiovascular relevance remains a testable translational hypothesis that requires route-specific pharmacokinetics, human target-engagement evidence, adequately powered periodontal trials, and eventual cardiovascular outcome studies.