A zinc-coordinated cascade-responsive therapeutic nanoassembly for remodeling the pathological microenvironment and restoring mitochondrial homeostasis in spinal cord injury.

Secondary injury after spinal cord injury (SCI) is sustained by coupled oxidative stress and inflammation, which drives neuronal apoptosis and bioenergetic failure. Here, a cascade-responsive Zn2+-centered nanoassembly (Zn-PC/PA@Gel) is constructed through stepwise coordination among Zn2+, procyanidin (PC), and polyarginine (PA) to form a core-shell architecture with a Zn2+-procyanidin core (Zn-PC) and a Zn2+-polyarginine shell (Zn-PA). In a reactive oxygen species (ROS) rich injury microenvironment, oxidation of guanidino groups in the polyarginine shell enables in situ nitric oxide (NO) release and weakens Zn2+ coordination, triggering controlled shell disassembly for early modulation of local inflammation and tissue microenvironment. The subsequent release of PC and Zn2+ provides continuous antioxidant protection. Zn2+ further restores mitochondrial quality control by regulating the STAT3-FOXO3a-SOD2 axis, thus enhancing mitochondrial autophagy, enhancing endogenous antioxidant defense, and restoring mitochondrial homeostasis and energy metabolism. In a mouse spinal cord contusion model, Zn-PC/PA@Gel mitigated inflammation and oxidative stress, alleviated the burden of mitochondrial dysfunction, protected neurons, and promoted motor recovery, resulting in a Basso Mouse Scale (BMS) score of 7.0 on day 28. Overall, these results support Zn2+ coordinated cascade therapy nanoassembly, which combines microenvironmental regulation with mitochondrial homeostatic recovery to reduce secondary injury after SCI and promote locomotor improvement.