<p>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.</p> Graphical Abstract <p></p>