Injectable Supramolecular Hydrogel Encapsulating CRISPR-Engineered MSCs Drives Synergistic Neuroprotection and Functional Recovery After Traumatic Brain Injury.

Traumatic brain injury (TBI) triggers complex secondary pathologies that lack effective treatments. While mesenchymal stem cell (MSC) transplantation is promising, it is severely limited by poor cell retention and survival. To address these challenges, we engineered a combinatorial platform comprising an injectable, self-healing supramolecular gelatin hydrogel (iGel) loaded with CRISPR-SAM-engineered "Super MSCs" (SPMSCs). These cells were programmed to endogenously multiplex the activation of neuroprotective factors IL-10 and FGF21. Our results demonstrate that the biomimetic iGel niche enhances SPMSC viability and sustained factor secretion compared to 2D cultures. In a murine TBI model, iGel-encapsulated SPMSCs exerted potent immunomodulatory effects, suppressing microglial inflammation and neuronal apoptosis while restoring blood-brain barrier integrity. Furthermore, the treatment promoted angiogenesis and endogenous neurogenesis. Consequently, treated mice exhibited reduced cerebral edema and lesion volume, alongside significant improvements in sensorimotor function and spatial memory. This study establishes a versatile, gene-editing-empowered biomaterial platform that overcomes critical bottlenecks in cell therapy for central nervous system injuries.