A lesion-responsive ZIF-8/zinc–myricetin nano-biointerface remodels mitochondrial–immune crosstalk for spinal cord repair

Abstract

Spinal cord injury (SCI) creates a hostile lesion microenvironment characterized by oxidative stress, mitochondrial dysfunction, inflammatory metabolic remodeling, and pyroptotic cell death, which collectively restrict neural repair. Here, we engineered a lesion-responsive ZIF-8/zinc–myricetin nano-biointerface, AST@ZIF-8@Zn-MYR, to coordinate redox regulation, mitochondrial protection, and immune microenvironment remodeling after SCI. Astaxanthin was encapsulated within a ZIF-8 core to improve cargo protection and enable pH/ROS-responsive release, while a zinc–myricetin coordination shell was constructed as a redox-active interfacial layer. The resulting nanoplatform exhibited a well-dispersed core–shell structure, responsive release behavior, broad-spectrum ROS-scavenging activity, and favorable cytocompatibility. In activated microglia, AST@ZIF-8@Zn-MYR reduced intracellular and mitochondrial oxidative stress, restored mitochondrial bioenergetics, alleviated glycolysis-biased immunometabolic remodeling, and attenuated inflammatory activation together with NLRP3/GSDMD-associated molecular signaling linked to pyroptosis. In oxidatively injured neuronal cells, the nano-biointerface preserved mitochondrial membrane potential, improved respiratory function, rebalanced mitochondrial dynamics, and supported neuronal survival and neurite outgrowth. In a rat SCI model, local administration attenuated acute oxidative-inflammatory injury, improved lesion microenvironment remodeling, preserved axon–myelin structures, and was associated with improved electrophysiological and locomotor outcomes. These findings identify AST@ZIF-8@Zn-MYR as a responsive bioactive nanomaterial that bridges interfacial redox chemistry and mitochondrial–immune regulation for spinal cord repair.