Nanoenzyme-Anchored Mitofactories Boost Mitochondrial Transplantation to Restore Locomotor Function after Paralysis Following Spinal Cord Injury

Abstract

Mitochondrial transplantation is a significant therapeutic approach for addressing mitochondrial dysfunction in patients with spinal cord injury (SCI), yet it is limited by rapid mitochondrial deactivation and low transfer efficiency. Here, high-quality mitochondria microfactories (HQ-Mitofactories) were constructed by anchoring Prussian blue nanoenzymes onto mesenchymal stem cells for effective mitochondrial transplantation to treat paralysis from SCI. Notably, the results demonstrated that HQ-Mitofactories could continuously produce vitality-boosting mitochondria with highly interconnected and elongated network structures under oxidative stress by scavenging excessive ROS. Furthermore, HQ-Mitofactories enabled efficient transfer of therapeutic mitochondria to injured neurons primarily via gap junctions, resulting in the restoration of mitochondrial homeostasis and thereby suppressing intracellular ROS burst and facilitating neuronal repair. After i.v. administration, HQ-Mitofactories migrated to the injured spinal cords of SCI mice and subsequently promoted neuronal regeneration and remyelination. Consequently, HQ-Mitofactory-treated mice successfully recovered locomotor function within 4 weeks, with 40% of the mice fully restoring walking after hindlimb paralysis. Conversely, untreated SCI exhibited completely abolished hindlimb movements. In light of real-time generation of vitality-boosting mitochondria even under oxidative stress and enabling targeted mitochondrial transfer, HQ-Mitofactories have promising therapeutic potential in the context of mitochondrial transplantation to reduce SCI-related paralysis, and more broadly impact the field of neuroregenerative medicine.