Mitochondria-targeted ROS-scavenging nanoreactor with dual-drug-loaded carbon dots for osteoarthritis therapy

Osteoarthritis (OA) pathology entails complex interactions among oxidative stress, chronic inflammation, cartilage degradation, and dysregulation of subchondral bone remodeling. Current therapeutic agents suffer from limited efficacy due to poor joint targeting and low bioavailability, highlighting the critical need for advanced drug delivery systems. In this study, a mitochondria-targeting reactive oxygen species (ROS)-scavenging nanoreactor (A@HP@SH/T) was developed for multi-mechanism OA repair. The nanoreactor is constructed using hollow mesoporous prussian blue (HMPB) as the carrier, loaded with carbon dots (AA CDs) co-assembled from astragaloside IV (AS-IV) and alendronate sodium (ALN), coated with diselenide-modified hyaluronic acid (Se-Se HA), and further conjugated with the mitochondrial-targeting ligand TPP. Through a temporal cascade of TPP-mediated mitochondrial anchoring, Se-Se HA ROS-responsive cleavage, and HMPB-mediated in situ protection and sustained release, AA CDs are precisely delivered to the lesion site, where they efficiently scavenge ROS and modulate mitochondrial homeostasis, thereby fundamentally breaking the vicious cycle of oxidative stress, chronic inflammation, and cartilage degradation within the joint. Additionally, the ALN component in AA CDs targets subchondral bone and modulates bone metabolism to reshape the local microstructure, offering both mechanical support and a beneficial nutritional microenvironment for cartilage regeneration. Both in vitro and in vivo studies confirmed that this system effectively restores mitochondrial homeostasis, alleviates inflammation, promotes cartilage differentiation, and regulates bone metabolism, thereby promoting OA repair. Collectively, this nanoreactor represents a highly promising strategy for the treatment of osteoarthritis.