ROS‐Targeted Nanomotor Therapy in OA: Cartilage Protection and Pain Relief

Osteoarthritis (OA) is a prevalent degenerative joint disease with limited effective treatment options. Joint inflammatory pain is a primary reason patients seek care, but systemic drug administration often causes severe side effects, while intra‐articular injection suffers from rapid clearance and poor tissue penetration. Herein, we develop nanozyme‐based Janus nanomotors loaded with metformin (MET) for reactive oxygen species (ROS)‐targeted therapy in OA. Leveraging intrinsic superoxide dismutase (SOD) and catalase (CAT) enzymatic activity, these nanomotors harness pathologically elevated ROS within the articular microenvironment as chemical fuel, achieving self‐propelled deep penetration into both cartilage and synovial tissue. This mechanism facilitates simultaneous on‐the‐move ROS scavenging and sustained deep‐tissue MET release, which further restores redox homeostasis and protects chondrocytes by regulating the NRF2/KEAP1 signaling pathway. Furthermore, the nanomotors can suppress nociceptive signaling in the dorsal root ganglia (DRG), thereby alleviating joint pain and improving mobility. This research offers a novel and efficient approach for cartilage protection and arthritis pain management. ROS‐responsive NM@MET nanomotors utilize elevated ROS in osteoarthritic joints to promote deep penetration into cartilage and synovium and enable sustained metformin release. By scavenging ROS, regulating NRF2/KEAP1 signaling, protecting chondrocytes, suppressing synovial inflammation, and attenuating nociceptive signaling, NM@MET alleviates pain and improves joint function.