Spatially Precise Neuron Formation via Hydrogel-Mediated Modulation of the Host Astrocyte Response

Abstract

The central nervous system exhibits limited capacity for regeneration following injury or disease. Although genetic and epigenetic reprogramming of non-neuronal cells into induced neurons offers a promising route for neuronal replacement and circuit reconstruction, its therapeutic potential remains constrained by low reprogramming efficiency and inadequate control over factor delivery. Here, we report a high-efficiency astrocyte-to-neuron reprogramming strategy enabled by ectopic expression of the transcription factor SOX2 delivered via adeno-associated viral vectors. We further engineered an implantable hybrid composite biomaterial that functions as a localized “reprogramming workshop”, performing sequential operations within the lesion microenvironment. Upon injection, the material forms a tissue-mimetic hydrogel that recruits endogenous astrocytes, concentrates reprogramming cues, and spatially confines their presentation. This system effectively entrapped astrocytes, guided their transition through a neuroblast-like intermediate state, and yielded robust populations of mature neurons. Incorporation of sustained valproic acid release further enhanced neuronal maturation. Together, these results present a design-led strategy for minimally invasive, tissue-optimized delivery of reprogramming factors and demonstrate a multifunctional biomaterial platform that significantly enhances neural repair potential.