Exosomes in knee osteoarthritis: molecular mechanisms and therapeutic rationale—a narrative review

Introduction Knee osteoarthritis (OA) affects over 374 million people globally, with projections reaching 539 million by 2035, yet current therapies remain palliative without disease-modifying effects. Exosomes, nano-sized extracellular vesicles from mesenchymal stem cells and other cells, offer cell-free regenerative and anti-inflammatory potential absent in traditional treatments. Objectives This narrative review aims to comprehensively summarize and critically evaluate the preclinical and clinical evidence on the therapeutic potential of exosomes in knee OA. Methods Structured literature search was performed across PubMed, Scopus, and Web of Science through March 2026 using terms including "exosome," "extracellular vesicle," "knee osteoarthritis," "cartilage regeneration," and "chondroprotection." Studies were selected based on mechanistic relevance, preclinical model quality (OARSI/Mankin scoring), clinical applicability, and peer-reviewed publication status, with manual reference list screening. Results Exosomes promote chondrocyte proliferation/migration, upregulate collagen (COL2A1)/aggrecan (ACAN), downregulate matrix metalloproteinases 13 (MMP-13)/A Disintegrin and Metalloproteinase with Thrombospondin Motifs 5 (ADAMTS5) via RAC-alpha serine/threonine-protein kinase (Akt)/Extracellular signal-regulated kinase (ERK) /AMP-activated protein kinase (AMPK)/Cyclin-dependent kinase 9 (CDK9) pathways, reduce Interleukin-1 beta (IL-1β)/Tumor necrosis factor-alpha (TNF-α), and improve OARSI/Mankin scores in OA models. Preclinical section notes no high-quality randomized controlled trials; early ExoFlo data show 75% to 82% pain relief but lack controls. Conclusions Exosomes hold promise for knee OA via multifaceted repair mechanisms but require standardized production, dosing randomized controlled trials, and regulatory approval to overcome manufacturing/reproducibility barriers for clinical use.