Polydeoxyribonucleotide and polynucleotide effects in musculoskeletal disorders: a systematic review

Importance The rising prevalence of degenerative musculoskeletal disorders and sports injuries has generated interest in regenerative medicine. Polydeoxyribonucleotide (PDRN) and polynucleotide (PN), extracted from salmonid (Salmonidae) germ-cell DNA, are biomacromolecules with extracellular matrix regenerative, pro-angiogenic, and anti-inflammatory properties. Objective We aimed to systematically analyze the clinical and preclinical research trends in PDRN and PN injection therapy in the musculoskeletal field. Evidence review Studies on PDRN and PN injection therapy published before March 2026 were retrieved from 10 databases (4 English-, 1 Chinese-, 1 Japanese-, and 4 Korean-language). Clinical studies comprised randomized controlled and clinical studies of adults with musculoskeletal and associated neurological pain; preclinical studies comprised experimental studies using musculoskeletal and related neurological pain models. Findings Of the 13,267 records retrieved, 38 (28 clinical and 10 preclinical studies) were included. The clinical studies reported disorders of the knee, shoulder, temporomandibular joint, wrist, ankle/foot, elbow, and spine, reporting overall improvements in pain (visual analog and numerical rating scales) and function (Western Ontario and McMaster Universities Osteoarthritis Index and maximum mouth opening); however, between-group significance varied by disease site and design, particularly with hyaluronic acid comparators. Preclinically, an adenosine A2A receptor-cAMP-PKA-CREB pathway has been proposed, with suppression of M1 and activation of M2 macrophages and upregulation of vascular endothelial growth factor, fibroblast growth factor, and transforming growth factor-β1, promoting type I collagen formation and tendon-to-bone junction reinforcement, while exerting anti-apoptotic effects via caspase-3/9 inhibition. These actions translated into biomechanical outcomes, such as load-to-failure and locomotor recovery. No serious adverse events attributable to PDRN or PN were reported in the available clinical studies; however, this finding should be interpreted cautiously, as adverse event assessment and reporting were incomplete and inconsistent across studies. Conclusion and relevance Available evidence suggests potential improvements in pain and function following PDRN/PN treatment; however, the certainty of the evidence remains limited because of methodological limitations, heterogeneous study designs, and inconsistent comparative effects. The limited quality and geographic representativeness of the evidence warrant rigorous, prospectively registered, large-scale, multinational randomized controlled trials. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420261363033, identifier CRD420261363033 and https://www.crd.york.ac.uk/PROSPERO/view/CRD420261363211, identifier CRD420261363211.