Synergistic redox and metabolic reprogramming by functionalized Prussian blue nanozymes for spinal cord injury repair

• Improved Therapeutic Context: Functionalized Prussian blue nanozymes (FPBNPs) enhance resveratrol delivery by improving solubility, lesion-site accumulation, and local bioavailability within injured spinal cord tissues. • Synergistic Redox–Metabolic Mechanism: FPBNPs combine enzyme-mimetic ROS scavenging with NAD + -dependent SirT1/SirT3 activation, promoting coordinated redox homeostasis and metabolic reprogramming. • Pathway-Level Neuroprotection: Activation of AMPK/SirT1 suppresses NF-κB–mediated neuroinflammation, while AMPK/SirT3–PGC-1α signaling restores mitochondrial function and bioenergetic balance. • Validated In Vivo and In Vitro Efficacy: FPBNPs enhance neuronal survival, promote axonal preservation (NF200 staining), modulate macrophage polarization (iNOS/Arg-1), and improve motor function recovery in murine spinal cord injury models. • Comprehensive, Translationally Relevant Platform: This work integrates nanozyme engineering with metabolic neurotherapy, providing a robust and versatile strategy for redox- and metabolism-driven neural repair. Spinal cord injury (SCI) initiates a self-perpetuating pathological cascade marked by metabolic failure, oxidative stress, and chronic neuroinflammation, which collectively impair neuronal repair and functional recovery. Here, we present a metabolism-targeted nanotherapeutic platform based on functionalized Prussian blue nanoparticles (FPBNPs) designed to interfere with this pathological cascade. Resveratrol (RES), a natural sirtuin activator, was encapsulated within PEG-modified Prussian blue nanozymes, enabling improved physicochemical stability, bioavailability, and penetration across the blood–spinal cord barrier. Leveraging the intrinsic enzyme-mimetic activity of PBNPs, FPBNPs scavenge reactive oxygen species (ROS) while modulating the cellular NAD + /NADH balance, thereby co-activating SirT1 and SirT3. Docking analyses suggested high-affinity interactions between RES and sirtuin catalytic domains, supporting its role as a metabolic modulator. FPBNPs exhibit H 2 O 2 -responsive release under oxidative conditions, attenuate oxidative damage, restore mitochondrial integrity, suppress inflammatory signaling, and promote neurite outgrowth. In SCI models, this dual-mode intervention leads to measurable improvements in motor function recovery. Collectively, this work introduces a redox–metabolic nanoplatform that facilitates coordinated regulation of cellular homeostasis, offering a potential therapeutic strategy for SCI.