Immunomodulatory therapies for osteoarthritis: from bench to bedside

Osteoarthritis (OA) of the knee, particularly in the medial compartment, is driven by chronic synovial inflammation, immune dysregulation, and progressive cartilage degeneration. Increasing evidence indicates that modifying the complete inflammatory microenvironment of the joint, rather than focusing solely on cartilage, is essential for achieving true disease-modifying outcomes. This review provides an integrated bench-to-bedside overview of emerging immunomodulatory cell and cell-derived therapies for knee OA, summarizing mechanistic foundations, preclinical findings, and early clinical progress. We first outline the pathological features of the OA joint, emphasizing macrophage polarization, T-cell subsets, and cytokine-driven pathways that sustain synovitis and extracellular matrix breakdown. The review then highlights three major therapeutic strategies: (I) immunomodulatory cell therapies, including cartilage-activated T cells (CATs), which aim to restore immune homeostasis; (II) extracellular vesicle (EV) and miRNA-based therapies that modulate inflammation, enhance chondrocyte survival, and promote matrix synthesis; and (III) peripheral blood stem cell (PBSC)-assisted regenerative approaches used in combination with arthroscopic procedures. Preclinical studies consistently demonstrate reduced inflammation, improved chondrogenesis, and enhanced structural repair across these modalities. We further summarize recent phase I/II clinical trials, which report favorable safety profiles and early clinical benefits, particularly for MSC-derived EVs and PBSC-based interventions. Nonetheless, long-term efficacy, manufacturing scalability, product heterogeneity, and regulatory complexity remain significant obstacles to widespread clinical translation. In conclusion, immunomodulatory cell and cell-derived therapies represent promising disease-modifying strategies for knee OA. Future progress will rely on standardized potency assays, optimized GMP manufacturing, robust clinical trial designs, and precision medicine approaches for targeted patient selection.