Engineering NO delivery system renormalizes the excitability of inhibitory interneurons after spinal cord injury via chloride extrusion.

Spinal cord injury (SCI)-induced severe neurological deficits arise from persistent ionic dysregulation and the dysfunction of inhibitory interneurons. Nitric oxide (NO) serves as a critical second messenger in ion channel modulation, yet its therapeutic potential in SCI-associated ionic dysregulation remains unexplored. In this study, an octahedral palladium nanozyme and L-Arg composite hydrogel (o-Pd/Arg(gel)) that achieves spatiotemporally controlled NO release while catalytically neutralizing the hazardous by-products of NO was engineered. o-Pd/Arg(gel) orchestrates dual neurovascular repair through augmenting endothelial nitric oxide synthase (eNOS) expression to enhance endothelial cell survival and stimulate brain-derived neurotrophic factor (BDNF) secretion, which further restores potassium chloride cotransporter KCC2 on the neuron cytoplasm, thereby rebalancing chloride extrusion capacity and renormalizing inhibitory interneuron excitability. The resultant ionic homeostasis recovery synergized with angiogenesis potentiation significantly improved sensorimotor function in SCI models. Our work not only deciphers the NO-KCC2-BDNF axis as a master regulator of neural inhibition circuitry but also establishes a proof-of-concept for ionic microenvironment-reprogramming therapeutics. This biomolecule-delivery paradigm advances both mechanistic understanding and translational potential in neurotrauma rehabilitation.