A supramolecular MgTA@MnO₂ nanozyme platform supports human spinal cord organoid structural integration and locomotor recovery via microenvironmental reprogramming

Background: Three-dimensional human spinal cord organoids (hSCOs) offer a compelling strategy for structural repair and neural network extension following spinal cord injury (SCI). Yet, their therapeutic viability is severely limited by the acute pathological microenvironment, where an intense oxidative storm causes rapid graft attrition and prevents neural integration. Creating a permissive redox niche is therefore critical to advancing organoid-based regenerative therapies.

Methods: We developed a supramolecular nanozyme (MgTA@MnO₂) to remodel the SCI microenvironment and support hSCO engraftment. This platform comprises a catalytic MnO₂ core-which clears Reactive Oxygen Species (ROS) and generates oxygen-encapsulated within a neuroprotective magnesium-tannic acid (Mg-TA) network. We co-transplanted the nanozymes and hSCOs into a rat contusion SCI model, assessing subsequent changes in local redox states, macrophage immunometabolism, and graft integration.

Results: Local delivery of MgTA@MnO₂ neutralized the acute oxidative burst, reduced lipid peroxidation, and upregulated anti-ferroptotic defense genes (Gpx4/Gpx1). This redox modulation protected hSCO grafts from Apoptosis and induced a metabolic shift in local macrophage/microglia populations, directing them away from hypoxia-associated glycolysis toward a reparative M2 phenotype. The resulting microenvironment attenuated glial scarring and supported the structural integration and axo-synaptic extension of the organoids. In vivo evaluations confirmed that the co-transplantation strategy reduced tissue cavitation and improved locomotor recovery in SCI rats.

Conclusion: The MgTA@MnO₂ nanozyme reconfigures the pathological SCI niche by correcting acute redox imbalances and shifting macrophage metabolism. This intervention establishes the permissive microenvironment necessary for hSCO survival and integration, offering a viable materials-driven strategy to improve Organoid therapies for severe central nervous system injuries.