Injectable microgels loaded with programmable WELNs based on mendelian randomization macroanalysis alleviate osteoarthritis by restoring the circadian rhythm

The development of interventional therapies that can effectively alleviate joint wear and promote cartilage regeneration is a major challenge in the clinical management of osteoarthritis (OA). This study aimed to develop an injectable microgel system with synergistic therapeutic functions. For decades, plant-derived exosome-like nanovesicles (PELNs) have gradually become an emerging direction in the research and development of disease intervention methods. To determine the most suitable PELNs in the treatment of OA, this study conducted mendelian randomization (MR) analysis to reveal the protective effect of watercress intake on OA progression from a wide range of dietary plants. The watercress-derived exosomes-like nanovesicles (WELNs) were isolated, and WELNs-CAP was modified with chondrocyte affinity peptide (CAP) to enhance its targeting to cartilage tissue, which was then encapsulated in methacrylic anhydride modified hyaluronic acid (HAMA) to construct injectable WELNs-CAP@HAMA microgel. Such microgel could provide lasting lubrication for joint friction during exercise and significantly reduce joint pain on the one hand; the sustained release of WELNs-CAP could effectively improve inflammation-induced mitochondrial dysfunction and maintain the normal metabolism of extracellular matrix (ECM), synergistically promote the regeneration and repair of cartilage. Mechanistically, omics sequencing and structural biology approach revealed that ferulic acid (FA), as the active ingredient in WELNs, could interact with the KLF10 to alleviate OA progression by restoring the disturbed circadian rhythm. Collectively, this study successfully developed an injectable microgel system based on PELNs, which integrated mechanical lubrication and biological repair, displaying great potential for OA treatment and clinical transformation prospects. • Watercress intake could prevent OA progression by Mendelian Randomization analysis. • Chemical programmed watercress-derived nanovesicles for protecting OA chondrocytes. • Injectable microgels loaded with functionalized nanovesicles for alleviating OA. • Mechanism exploration based on multi-omics and structural biology analysis. • Ferulic acid reversed the progression of OA by regulating the circadian rhythm.