Zn-driven metformin conjugated with siRNA attenuates osteoarthritis progression by inhibiting NF-κB signaling and activating autophagy.

Osteoarthritis (OA) is a type of joint disease that influences millions of individuals. Regrettably, effective treatment for OA is currently unavailable. The challenge lies in the deep location of chondrocytes within the dense cartilage matrix that hinders the delivery and efficiency of clinical OA drugs. To overcome this obstacle, the present study proposed a hybrid nanodrug by Zinc(II) metal-drug coordination-driven self-assembly as highly efficient delivery system. This nano-assembly formulations possessed the ability to deliver two types of drugs, namely metformin (Met) and therapeutic genes (p65 siRNA). Results showed that this nano-assembly not only exhibited positive charge-driven anchoring to the cartilage matrix and effective drug delivery capacity, but also synergistically inhibited NF-κB activity and activates autophagy of OA chondrocytes, thus safeguarding the cartilage. The successful achievement of this project not only contribute to the advancement of research on bio-nanomaterials for treating OA, but also establish a robust theoretical foundation for realizing promising and functional integration of nanomedicine targeting OA.