Bio‐Orthogonal Engineering of Neural Stem Cells with Membrane‐Bound Microsatellites for Enhanced Brain Repair

Abstract Regulating the differentiation of implanted stem cells into neurons is crucial for stem cell therapy of traumatic brain injury (TBI). However, due to the migratory nature of implanted stem cells, precise and targeted regulation of their fate remains challenging. Here, neural stem cells (NSCs) are bio‐orthogonally engineered with hyaluronic acid methacryloyl (HAMA) microsatellites capable of sustained release of differentiation modulators for targeted regulation of their neuronal differentiation and advanced TBI repair. By employing bio‐orthogonal covalent reactions and optimizing the microsatellite size, HAMA microsatellites can stay on membranes for over 10 days owing to the minimal detachment or endocytosis. These microsatellites can thus migrate together with engineered NSCs and release modulators around the cells, actively inducing 45.1% of NSCs to differentiate into neurons compared to only 18.8% for normal NSCs. These microsatellite‐engineered stem cells improve brain tissue repair and enhance behavioral recovery in TBI rats after implantation. This strategy holds promise for the advanced treatment of TBI and other neurodegenerative diseases.