Bio‐Propelled Stomatocyte Nanomotors with Glutathione‐Responsiveness for Osteoarthritis Treatment

ABSTRACT Pharmacological intervention is a primary therapeutic strategy for Osteoarthritis (OA), however, improving the bioavailability of therapeutic agents remains a significant challenge. In this study, we developed oxygen‐propelled, glutathione (GSH)‐responsive stomatocyte nanomotors (MTX/MnO 2 ‐GSH‐stomatocytes) for osteoarthritis (OA) treatment. First, polymersomes were assembled composed of block copolymers containing a GSH‐cleavable disulfide linker, which were loaded with the therapeutic agent methotrexate (MTX) into their hydrophilic domain. Upon dialysis‐induced shape change bowl shaped stomatocytes were formed with manganese dioxide (MnO 2 ) particles encapsulated into the nanocavity with high loading efficiency. Within the OA microenvironment, MnO 2 decomposed the inflammatory hydrogen peroxide (H 2 O 2 ), generating an O 2 gradient that propelled the nanomotors and enabled chemotactic movement for targeted cargo delivery. Meanwhile, after cellular uptake elevated GSH levels cleaved the disulfide linkers, inducing the collapse of the stomatocyte structure and the rapid release of MTX. The motility and targeted release behavior of the nanomotors were systematically evaluated both in vitro and in vivo. Experimental results demonstrated that these nanomotors effectively alleviated oxidative stress, inflammation, and cartilage degradation, while exhibiting negligible adverse effects. Overall, this study presents a promising GSH‐responsive, nanomotor‐based strategy for enhanced osteoarthritis therapy.