Zinc-Myricetin Nanoshell Rewires Mitochondria and Immunity to Repair Spinal Cord Injury

Spinal cord injury has long been one of the most stubborn challenges in medicine, and a new study published in Materials Today Bio suggests that the key to unlocking repair may lie not in the neurons themselves but in the chaotic microenvironment that forms around them after trauma. Researchers led by Yuqi Zhao, Huimin Hu, and Cheng Ju at Xi’an Jiaotong University have engineered a sophisticated core-shell nanoparticle, dubbed AST@ZIF-8@Zn-MYR, that responds directly to the acidic and oxidizing conditions of an injured spinal cord. In rat models of contusion injury, the material reduced oxidative stress, calmed overactive immune cells, preserved mitochondria, and ultimately improved hindlimb locomotion over eight weeks of recovery.

The rationale behind the design stems from a growing recognition that secondary injury, rather than the initial mechanical blow, determines how much function is ultimately lost. Within hours of trauma, the lesion site becomes flooded with reactive oxygen species, mitochondrial membranes collapse, and immune cells shift into a destructive inflammatory mode. Mitochondrial dysfunction sits at the center of this cascade. Damaged mitochondria leak superoxide, which activates the NLRP3 inflammasome, drives gasdermin D-associated pyroptotic signaling, and pushes microglia and macrophages into a glycolysis-dominant, pro-inflammatory state. Because these processes feed one another, single-target drugs have consistently underperformed in preclinical models.

The team’s solution was to combine two natural compounds with complementary bioactivities inside a single responsive vehicle. Astaxanthin, a carotenoid with potent mitochondrial-protective and antioxidant properties, was encapsulated within zeolitic imidazolate framework-8, a pH-sensitive metal-organic framework that degrades under the pathological acidosis characteristic of injured tissue. Myricetin, a flavonoid known to regulate mitochondrial homeostasis and suppress inflammasome activation, was then coordinated with zinc ions to form a metal-phenolic outer shell. The result is a particle of roughly 172 nanometers in hydrodynamic diameter that carries both a protected drug reservoir and a redox-active surface interface.

Characterization confirmed the architecture in detail. Transmission electron microscopy revealed polyhedral particles with roughened surfaces after coating, while elemental mapping showed carbon, nitrogen, oxygen, and zinc distributed throughout. X-ray diffraction demonstrated that the ZIF-8 crystalline framework survived shell formation, and X-ray photoelectron spectroscopy verified the surface chemical states. Drug loading was quantified by high-performance liquid chromatography at 7.28 weight percent astaxanthin for the uncoated core and 1.47 weight percent for the full construct, with myricetin loading of approximately 12.03 percent. Release experiments showed the platform’s defining feature: at physiological pH 7.4, cargo liberation remained limited, but acidic conditions and hydrogen peroxide dramatically accelerated release of both astaxanthin and myricetin, with combined acidic and oxidative conditions releasing 66.9 percent of myricetin within 72 hours.

The zinc-myricetin shell proved to be far more than a passive coating. Electron paramagnetic resonance showed that the coated particles quenched superoxide and hydroxyl radicals more effectively than the uncoated core, and colorimetric assays confirmed concentration-dependent scavenging of ABTS, DPPH, hydrogen peroxide, and hydroxyl radicals. Zinc release, measured by ICP-MS, rose from about 9 micromolar at neutral pH to nearly 25 micromolar under combined acidic and oxidative stimulation, a range that primary hippocampal neurons tolerated without significant viability loss. The authors are careful to note that without isolated shell-only controls, the individual contributions of zinc coordination and myricetin chemistry cannot be formally separated, and the data do not establish true synergy between components.

In cell studies, the nanoplatform reshaped the behavior of activated microglia. When BV2 cells were stimulated with lipopolysaccharide, mitochondrial superoxide surged, membrane potential collapsed, and glycolytic activity climbed. Treatment with the full nanoparticle suppressed these changes more effectively than free drugs or the uncoated core, restoring respiratory parameters measured by Seahorse extracellular flux analysis and shifting the cells away from a CD68-positive, CD86-positive inflammatory phenotype toward a CD206-positive reparative one. Levels of NLRP3, gasdermin D, and interleukin-1 beta fell markedly, though the authors emphasize that total gasdermin D abundance does not prove inhibition of pyroptotic cell death itself, since the cleaved pore-forming fragment was not assessed.

Neuronal cells benefited in parallel. In PC12 cells exposed to hydrogen peroxide, the nanoparticles entered cells progressively over 36 hours, reduced cytosolic and mitochondrial reactive oxygen species, restored membrane potential, and repaired mitochondrial ultrastructure as visualized by electron microscopy. Bioenergetics recovered too: basal respiration, ATP-linked respiration, maximal respiration, spare respiratory capacity, and cellular ATP all rebounded. The treatment also rebalanced mitochondrial dynamics, restoring the fusion proteins MFN1 and MFN2 and the deacetylase SIRT3 while suppressing the fission protein DRP1. In primary hippocampal neurons, the platform improved survival and increased both the number and total length of neurites after oxidative challenge, suggesting preservation of growth-associated phenotypes permissive for structural repair.

The in vivo results tied the cellular story to functional recovery. Locally injected into the lesion immediately after clip-compression injury at the T8 segment, the nanoparticles prolonged early astaxanthin retention in tissue without progressive zinc accumulation through day seven. Chemiluminescence imaging on day three showed the strongest reduction in lesion oxidative burden among all treatment groups. By day seven, flow cytometry of dissociated tissue revealed that resident microglia, which outnumbered infiltrating macrophage-lineage cells roughly seventeen-fold, had shifted away from CD86-positive inflammatory activation toward CD206-positive reparative markers. Caspase-3 signals fell, NeuN-positive neurons were preserved, and NLRP3 and gasdermin D signals in CD68-positive cells declined. Transcriptome sequencing independently supported these observations, with enrichment changes in NOD-like receptor signaling, IL-17 signaling, and extracellular matrix-receptor interaction pathways, validated for selected genes by quantitative PCR.

Eight weeks after injury, the structural gains translated into measurable function. Treated animals showed higher Basso, Beattie, and Bresnahan locomotor scores that improved progressively over the observation period, along with larger motor evoked potential amplitudes, shorter response latencies, preserved muscle wet weight and fiber area, stronger electromyographic activity, and more regular gait patterns. Histology revealed denser Nissl-positive neurons, greater Luxol fast blue-positive myelin, more myelinated axons with reduced g-ratios on electron microscopy, and constructive remodeling of laminin and fibronectin deposition at the lesion. Major organ histology, blood counts, and serum chemistry showed no treatment-associated abnormalities within the eight-week window, though the authors caution that long-term degradation, biodistribution, and clearance of the zinc-containing framework remain unresolved questions for translation.

The study’s most important contribution may be conceptual rather than a specific therapy. Rather than targeting a single pathological event, the nano-biointerface treats the lesion as an interconnected system in which redox balance, mitochondrial bioenergetics, immune metabolism, and inflammatory signaling must be remodeled together. The authors themselves are notably restrained about causality: mitochondrial restoration is presented as a convergent treatment-associated feature, not a proven upstream driver, and no formal dose-ranging or component-perturbation experiments were performed. Still, the demonstration that a single responsive material can coordinate mitochondrial-immune crosstalk across cell types and produce durable functional recovery offers a compelling template for microenvironment-oriented spinal cord repair, and a reminder that the next generation of neuroregenerative biomaterials may need to be as dynamic as the injuries they confront.

Subject of Research: A lesion-responsive ZIF-8/zinc-myricetin nano-biointerface that remodels mitochondrial-immune crosstalk for spinal cord injury repair

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

Article References: Zhao, Y., Xia, Z., Xie, T., Liu, R., Liu, S., Luo, R., Wang, S., Huang, D., Yan, L., Hu, H., & Ju, C. (2026). A lesion-responsive ZIF-8/zinc–myricetin nano-biointerface remodels mitochondrial–immune crosstalk for spinal cord repair. Materials Today Bio, 41, Article 103683. https://doi.org/10.1016/j.mtbio.2026.103683

Image Credits: AI Generated

DOI: 10.1016/j.mtbio.2026.103683

Keywords: spinal cord injury, nanoparticles, ZIF-8, astaxanthin, myricetin, mitochondria, microglia, NLRP3 inflammasome, oxidative stress, metal-organic framework, neuroinflammation, biomaterials