Cartilage organoids bridging bench to bedside: A steroid-free strategy for early osteoarthritis repair.

Background: Osteoarthritis (OA) is the most prevalent degenerative joint disease, characterized by progressive cartilage loss, chronic inflammation, and functional decline. Current intra-articular therapies, most notably corticosteroids, provide transient pain relief but accelerate cartilage catabolism upon repeated administration. A critical need remains for steroid-free interventions that can simultaneously suppress inflammation and promote cartilage regeneration. Methods: We developed a translational strategy integrating sinomenine, a natural alkaloid with immunomodulatory properties, into bone marrow mesenchymal stem cell (BMSC)-derived cartilage organoids. The anti-inflammatory and pro-chondrogenic effects of sinomenine were evaluated under lipopolysaccharide-induced stress Results: Sinomenine at a concentration of 20 μg/mL mitigated inflammation by suppressing the expression of tumor necrosis factor alpha and interleukin 6 while enhancing chondrogenesis in BMSCs. Sinomenine-treated organoids (sino-organoids) exhibited increased glycosaminoglycan content, reduced MMP13 expression, and stable SOX9 and COL-II expression profiles. Sino-organoids achieved superior defect filling, organized matrix deposition, and attenuated inflammatory infiltration in rat cartilage defects. Clinically, sinomenine injections were noninferior to corticosteroids across Western Ontario and McMaster Universities Osteoarthritis Index, visual analog scale, Timed Up and Go test, 20-m walk, and magnetic resonance imaging outcomes during a 24-month period, while avoiding the cartilage loss progression observed in the corticosteroid arm. Conclusions: This study established sinomenine-enhanced cartilage organoids as a steroid-free therapeutic platform for early OA. We united pharmacological immunomodulation with organoid-based regeneration to develop a bench-to-bedside pipeline that achieved comparable efficacy to corticosteroids while offering superior structural protection. These findings highlight a paradigm shift in OA management, suggesting that traditional bioactive compounds can be harnessed with organoid technology to deliver durable, regenerative, and clinically viable therapies. Trial registration: ClinicalTrials.gov Identifier: NCT05764304.