Spatiotemporal Drug Delivery via a Neonatal Spinal Cord ECM Hydrogel for Biomimetic Microenvironment Remodeling After Spinal Cord Injury

ABSTRACT Spinal cord injury (SCI) creates an inhibitory microenvironment at the lesion site, where depositions of inhibitory molecules, loss of neurotrophic factors, and glial scar formation collectively impede axonal regeneration. The extracellular matrix (ECM) of the neonatal mouse spinal cord contains proteins that promote neural development and axon growth, and certain ECM‐associated proteins drive scarless healing and functional recovery after neonatal SCI. In this study, we prepare a decellularized spinal cord ECM from neonatal (DNSCM) hydrogel that retains key ECM components from neonatal mice. Using Tandem Mass Tag (TMT)‐based quantitative proteomics, we find that, compared with adult mice, neonatal after SCI show upregulation of LAMB2—a key protein that promotes axonal growth—and downregulation of the inhibitory protein CSPG. Capitalizing on this discovery, we engineer a combined therapeutic system (D/L/I) by loading DNSCM hydrogel with LAMB2 and CSPG antagonist membrane‐permeable intracellular sigma peptide (ISP). When transplanted into adult mice with SCI, the D/L/I system achieves sustained drug release, effectively remodels the inhibitory microenvironment, and robustly promotes axonal regeneration, motor function recovery, and bladder function restoration. Importantly, this biomimetic strategy, which recapitulates the developmental and regenerative ECM microenvironment of homologous juvenile mammals, offers a promising therapeutic approach for the clinical treatment of SCI patients.