Abstract

Repairing spinal cord injury (SCI) remains hindered by two major unmet challenges: the inability to precisely reconstruct irregular lesion cavities, where tissue contraction and collapse disrupt anatomical continuity, and the lack of effective platforms for stable and localized delivery of fragile therapeutics such as exosomes, whose rapid clearance severely limits efficacy. Addressing these bottlenecks requires biomaterials that can simultaneously rebuild three-dimensional structure and orchestrate a pro-regenerative microenvironment. Here, we present a morphology-adaptive injectable microporous annealed particle scaffold (MS) for localized and long-term release of human umbilical cord MSC-derived exosomes (hucMSC-Exo). GelMA/SFMA microspheres were fabricated via solvent-free microfluidic electrospraying combined with liquid nitrogen-assisted cryo-processing, preserving exosome bioactivity. This “disassemble-and-reassemble” approach enables minimally invasive injection of microspheres into irregular lesion cavities, followed by body temperature-induced annealing and in situ photocuring to form a mechanically stable, interconnected three-dimensional scaffold, which supports cell infiltration, nutrient diffusion, and sustained exosome release. In vivo , MS@Exo suppressed inflammation and scar formation, enhanced angiogenesis, and promoted neuronal survival, axonal regeneration, and myelination, ultimately achieving superior functional recovery over MS or Exo alone, demonstrating a clear synergistic effect. Transcriptomic profiling further revealed that MS@Exo reprogrammed gene expression by downregulating extracellular matrix- and collagen-related pathways while upregulating neuronal, synaptic, and ion channel signaling networks, thereby shifting the repair process from an inflammatory-proliferative phase toward a differentiation-remodeling phase. Collectively, MS