Nitric oxide (NO), a gaseous signaling molecule, is increasingly recognized for its central role in the pathophysiology of dental and oral diseases. Dysregulation of nitric oxide synthase (NOS) and consequent impairment of endogenous NO production have been implicated in a range of oral conditions. Accordingly, exogenous NO therapy has garnered significant interest due to its broad-spectrum antibacterial, potent anti-inflammatory, tissue-regenerative, and potential antitumor effects. This review provides a comprehensive overview of therapeutic advances in exogenous NO for dental and oral diseases, focusing on underlying mechanisms, such as modulation of the cyclic di-guanosine monophosphate pathway, mediation of S-nitrosylation, activation of the soluble guanylate cyclase–cyclic guanosine monophosphate–protein kinase G pathway, and regulation of the c-Jun N-terminal kinase/mitogen-activated protein kinase pathway. Collectively, these mechanisms confer antimicrobial efficacy, immunomodulation, enhanced periodontal and pulpal tissue repair, and apoptosis induction in oral cancer cells. Various NO delivery platforms, including nanocarriers, hydrogels, implant coatings, and microneedles, are reviewed for their efficacy and application in managing periodontitis, peri-implantitis, dental caries, endodontic and periapical diseases, oral ulcers, orthodontic tooth movement, and oral cancer. Although most of the current evidence is derived from preclinical studies and substantial challenges remain with respect to dosing accuracy and delivery specificity, the unique multitarget properties of exogenous NO highlight its considerable promise as an adjunctive strategy in dental medicine. This review seeks to provide a comprehensive overview that not only advances fundamental understanding of exogenous NO but also promotes its clinical translation for improved management of dental and oral diseases.
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