Inositol hexaphosphate-based neuroinductive hydrogel promotes metabolic-epigenetic signaling to repair spinal cord injury

Abstract Spinal cord injury (SCI) repair is fundamentally constrained by a hostile post-injury microenvironment characterized by oxidative stress, metabolic dysfunction, and aberrant stem cell fate decisions. This study presents a dual-crosslinked neuroinductive hydrogel engineered for the controlled co-release of inositol hexaphosphate (IP6) and magnesium ions (Mg2+). This dynamic-covalent dual-network architecture combines injectability, swelling resistance, and mechanical compliance matched to native spinal cord tissue. Within the 3D matrix, IP6 and Mg2+ are anchored and gradually released via dynamic coordination bonds. Specifically, IP6 functions as a metabolic regulator, triggering AMP-activated protein kinase (AMPK) phosphorylation, elevating intracellular adenosine triphosphate (ATP) levels, and inducing endoplasmic reticulum Ca2+ release. The resulting Ca2+/calmodulin-dependent protein kinase-Ⅱ (CAMKII) cascade promotes phosphorylation and nuclear translocation of the epigenetic coactivator p300, enhances histone acetylation and selectively activates neuron-associated gene expression while suppressing astrocytic differentiation. In parallel, the hydrogel mitigates inflammatory and oxidative stress and supports vascular repair, thereby stabilizing the injury microenvironment to preserve neuroinductive signaling in vivo. Transplantation of the neural stem cell (NSC)-laden hydrogels into a rat SCI model resulted in robust neuronal regeneration, axonal reconnection, and significant recovery of motor and bladder function. This work establishes a metabolically and epigenetically instructive biomaterial strategy for in situ neural regeneration, offering a new paradigm for stem cell-based SCI therapy.