Hybrid exosomal nanomotors convert pathological ROS into transport-driving cues to enhance cartilage accumulation in osteoarthritis
- Kai Huang
- Hui-Zhi Liu
- Yuan Liu
- Jia-Yan Lyu
- Qing-Yi Zhang
- Zi-Yuan Feng
- Zi-Lin Wang
- Hui Dong
- Rong Nie
- Yi-Wen Zhang
- Yue-Qi Zhang
- Yi Zeng
- Hui-Qi Xie
- Zhou Zhou
- Bin Shen
2026-08-29
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.