Hybrid exosomal nanomotors convert pathological ROS into transport-driving cues to enhance cartilage accumulation in osteoarthritis

Abstract Osteoarthritis (OA) remains difficult to treat because drug transport within cartilage is restricted by its dense extracellular matrix and rapid joint clearance. Here we show that hybrid exosomal nanomotors (CAP-Mn/140@hyExos) convert pathological reactive oxygen species (ROS) into transport-driving cues to overcome diffusion-limited transport within cartilage. In the oxidative OA microenvironment, manganese dioxide (MnO₂) catalyzes H₂O₂ decomposition, driving ROS-responsive transport, while a cartilage-targeting peptide enhances matrix interaction, together promoting cartilage accumulation. This strategy achieves deeper penetration (~140 μm), greater cellular uptake (~2.5-fold), and prolonged intra-articular retention (~30% remaining at two weeks). Enhanced transport enables efficient intracellular delivery of miR-140 and MnO₂ nanoparticles, attenuating oxidative stress and promoting cartilage regeneration. In a rat OA model, this therapeutic strategy improves gait performance, restores subchondral bone microarchitecture, and suppresses OA progression. These findings establish pathological microenvironments as endogenous drivers of intratissue drug transport, providing a transport-regulated strategy for drug delivery in transport-restricted tissues.