Nano-primed reprogrammed neurons suppress the glial scar and facilitate axonal regeneration after spinal cord injury.

Spinal cord injury (SCI) often results in permanent sensory-motor deficits due to the formation of an inhibitory glial scar and the massive loss of neurons. Chemical reprogramming into induced neuron-like cells (iNLCs) is a promising therapy, but free small molecules (like curcumin) cause high cytotoxicity and low conversion. Additionally, graft survival in the harsh SCI microenvironment remains poor. We developed curcumin-loaded PLGA nanoparticles (Cur-PLGA-NPs) for sustained release. Human fibroblasts were reprogrammed into iNLCs using CHIR99021 and Cur-PLGA-NPs by stages, validated by immunofluorescence, flow cytometry, RT-qPCR, and bulk-RNA sequencing. These iNLCs were encapsulated in a biomimetic 3D fibrin hydrogel and implanted into a rat complete SCI model to evaluate cell survival, microenvironmental remodeling, and functional recovery. In vitro, the sustained release effect of Cur-PLGA-NPs mitigated curcumin toxicity, achieving an 86.0% reprogramming efficiency of mature neurons. Transcriptomics confirmed fibroblastic gene silencing and neuronal network activation. In vivo, the composite scaffold ensured long-term graft retention, increasing rat survival to 100%. At 8 weeks post-SCI, treated rats exhibited remarkable motor recovery and gait correction. Histology demonstrated significant glial scar attenuation and robust regeneration of NF200-positive nerve fibers bridging the lesion. The integration of sustained release from nanoparticles and a biomimetic hydrogel effectively mitigates the toxicity of small molecules and ensures robust cell engraftment. This strategy effectively remodels the pathological microenvironment, promotes axon regeneration, and restores motor function, providing a promising and comprehensive therapeutic approach for severe SCI.