An Epigenetic Fate Converter Based on Nuclei‐Targeting Lipid Nanoparticles Drives Neuronal Programming of Stem Cells for Spinal Cord Repair

Abstract

Spinal cord injury (SCI) often causes permanent neurological deficits due to limited neuron regeneration and glial scar formation. Stem cell therapy is promising, but transplanted stem cells often differentiate into astrocytes rather than neurons under inflammatory conditions. To address this, a nuclei‐targeting, histone acetylation–regulated lipid nanoparticle (LNP) was developed to direct stem cell fate. The LNP was functionalized with the MPG cell‐penetrating peptide (LNP‐MPG) for nuclei‐targeting, greatly enhancing the transfection efficiency of dental pulp stem cells (DPSCs). It delivered a high‐molecular‐weight FGF2 (HMW‐FGF2) plasmid to activate nuclear FGFR1, promoting CBP/p300‐dependent histone H3 acetylation. This epigenetic modulation drove DPSCs to differentiate into neurons rather than astrocytes even under inflammatory conditions. In a mouse SCI model, DPSCs transfected with HMW‐FGF2@LNP‐MPG significantly promoted neuronal regeneration, reduced glial scarring, and improved motor function. Mechanistically, we further confirmed that the engineered DPSCs formed functional synaptic integration with V2a‐linked circuitry, the core component of the spinal locomotor central pattern generator; specific ablation of V2a interneurons completely abolished the motor functional recovery induced by DPSC transplantation. These results demonstrate that this histone acetylation–regulated nano‐converter effectively redirects stem cell fate and improves functional recovery, offering a promising therapeutic approach for SCI repair.