A temporally responsive anti-scarring and pro-neuronal differentiation dual-targeting composite hydrogel fabricated via AI-assisted design and loaded with neural stem cells for spinal cord injury repair

Spinal cord injury (SCI) is a highly disabling central nervous system disorder. Tissue engineering strategies utilizing multifunctional hydrogels for neural stem cell (NSC) delivery represent a promising therapeutic direction for SCI. Herein, a temporally responsive dual-targeting multifunctional hydrogel (EnpMG-bSH) for NSC delivery is reported. An artificial intelligence (AI)-assisted designed TGF-β-targeted lysosome-targeting chimera (LYTAC) peptide EndoP144 is released in a temporally controlled manner in response to the gradually elevated matrix metalloproteinase-2 (MMP-2) in the SCI lesion site, enabling precise transforming growth factor-β (TGF-β) regulation. Adhesive silk fibroin nanoparticles anchored with si- Notch1 -loaded hybrid exosomes are incorporated to induce neuronal differentiation of NSCs, support synaptic remodeling and exert concurrent immunomodulatory effects. This system attenuates glial scarring by downregulating the TGF-β signaling pathway in astrocytes, modulates the differentiation of NSCs via targeted modulation of the Notch1 pathway, and reshapes the local inflammatory microenvironment toward an anti-inflammatory phenotype, significantly improving locomotor and sensory recovery in SCI mice. Collectively, the AI-assisted EnpMG-bSH hydrogel-NSCs complementary therapeutic strategy provides a potential framework for coordinated local treatment of SCI.