Synergistic mitochondrial homeostasis regulation and cholinergic circuits reconstruction via a one-step synthesized multifunctional hydrogel facilitates spinal cord injury repair

Neural Stem Cells (NSCs) possess significant potential to form new neural networks. However, following spinal cord injury (SCI), mitochondrial dysfunction leads to the excessive accumulation of reactive oxygen species (ROS), which severely impairs the neuronal differentiation of endogenous NSCs and thus hinders neural regeneration. Here, we report a multifunctional hydrogel, Poly(LA-Cho)/SS31 (PLCS), synthesized in one step using lipoic acid (LA), choline bicarbonate, and elamipretide (SS31). PLCS hydrogel exhibits injectability, self-healing ability, tissue adhesion, and sequential drug release. Initially, SS31 is released preferentially to scavenge mitochondrial ROS and alleviate mitochondrial dysfunction. Subsequently, LA is continuously to scavenge ROS. Notably, PLCS hydrogel not only promotes NSCs differentiation into cholinergic neurons but also increases acetyl-CoA levels and supplies choline, offering necessary substrates for acetylcholine synthesis in newly formed cholinergic neurons to support their functional maturation. The PLCS hydrogel achieves robust nerve regeneration and significantly improves motor, sensory, and bladder functions in rat models of SCI. RNA sequencing suggests the PI3K-Akt pathway may contribute to spinal cord repair. This one-step synthesis method without catalysts and organic solvents can effectively integrate physical and biological functions of hydrogel, through simple mixing, offering a highly promising strategy for the clinical translation of SCI treatment and other central nervous system injuries. • This catalyst- and solvent-free, one-step synthesis is a promising non-toxic, cost-effective, and clinically translatable method. • This PLCS hydrogel is injectable, adhesive, and self-healing, constructing a microenvironment for neural regeneration. • LA and Cho, as bioactive molecules, constitute the PLCS’s backbone, enabling an integrated "scaffold-as-medicine" strategy. • Synergistic regulation of mitochondrial homeostasis and reconstruction of cholinergic circuits contribute to repairing SCI.