Nerve‐Derived Extracellular Matrix Promotes Neural Differentiation of Bone Marrow Stromal Cells and Enhances Interleukin‐4 Efficacy for Advanced Nerve Regeneration

Abstract Facilitating neuronal differentiation of stem cells and microenvironment remodeling are the key challenges in cell‐based transplantation strategies for central nervous system regeneration. Herein, the study harnesses the intrinsic pro‐neural differentiation potential of nerve‐derived extracellular matrix (NDEM) and its specific affinity for cytokines to develop an NDEM‐gelatin methacryloyl(gelMA)‐based bifunctional hydrogel delivery system for stem cells and cytokines. This system promotes the neural differentiation of bone marrow stromal cells (BMSCs) and optimizes the therapeutic index of Interleukin‐4 (IL‐4) for spinal cord injury (SCI) treatment. It is observed that incorporating NDEM into the hydrogel system intrinsically promotes BMSC differentiation into neuron‐like cells and effectively regulates IL‐4 release kinetics to match the neural reconstructing timeframe. Further analysis reveals that trace amounts of endogenous basic fibroblast growth factor (bFGF) detected in NDEM exhibit a potent effect in promoting neural differentiation. The sustained release of IL‐4 from the NDEM significantly encourages macrophage polarization toward the M2 phase, optimizing the transplant microenvironment throughout the reconstruction process. This study demonstrates an NDEM‐based optimization strategy for hybrid hydrogel to achieve synchronized delivery of stem cells and cytokines in regenerative medicine applications.