A novel apoferritin nanocage with ECM promoting, ferroptosis suppressing and inflammation targeting property for osteoarthritis therapy

Osteoarthritis (OA) currently affects over 15% of the global population. However, OA management primarily focuses on symptom relief, with a lack of targeted and effective therapeutic strategies. SM04690 (Adavivint, Lorecivivint) represents a small molecule with promising potential as a novel agent for cartilage regeneration and pain relief in OA treatment, Phase III clinical trials are currently underway. This study explores its previously unexamined effects on regulating chondrocyte extracellular matrix (ECM) function. However, its targeted delivery to the inflammatory cells remains a challenge; also, ideal therapeutic agent for OA requires to be multi-functional, e.g. suppressing ferroptosis in chondrocytes. In the current study, we designed an ApoFerritin nanocage loaded with SM04690 (SM04690@ApoFn) for OA therapy. In vitro study showed that SM04690 may have chondro-regenerative effect similar to kartogenin (KGN) but works at much lower concentrations. SM04690@ApoFn demonstrated good biocompatibility both in vitro and in vivo. The following studies revealed that SM04690@ApoFn may effectively promote ECM metabolism in chondrocytes, it may also suppress ferroptosis; meanwhile, it may have the ability to targeting the inflammatory chondrocytes through binding to transferrin receptor (TfR). In vivo study demonstrated that SM04690@ApoFn may alleviate the progression of OA in mice. In conclusion, the multifunctional SM04690@ApoFn nanocage shows great potential for OA therapy by promoting ECM metabolism, suppressing ferroptosis and targeting inflammatory chondrocytes.