Mesenchymal Stem Cell-Lysate Sustained-Release Nano-Hydrogel Alleviates Spinal Cord Injury by Inhibiting Ferroptosis and Mitochondrial Intrinsic Apoptosis

Background: Spinal cord injury (SCI) has emerged as a major challenge to global public health due to its low recovery rate and high disability rate, making the development of novel therapeutic approaches imperative. Mesenchymal stem cell lysate (MSC-lysate) not only retains the regenerative potential of mesenchymal stem cells (MSC) but also avoids many potential risks associated with MSC, serving as a safe and effective novel strategy for SCI treatment. However, its therapeutic efficacy and underlying mechanisms in SCI remain unclear. Methods: First, a MSC-lysate (MSC derived from dental pulp stem cells) sustained-release nanohydrogel composite system (DL@ZIF-8@PF-127) was fabricated using MSC-lysate, ZIF-8, and PF-127. The anti-inflammatory, antiapoptotic, and ferroptosis-inhibitory effects of the DL@ZIF-8@PF-127 composite system were evaluated using a SCI animal model and a H2O2-induced cellular model. Subsequently, Western blot, immunohistochemistry, Enzyme-Linked Immunosorbent Assay, real-time quantitative polymerase chain reaction (RT-qPCR), and JC-1 assays were employed to detect the expression of proteins related to the Nrf2/HO-1/P65 pathway, mitochondrial membrane potential, and apoptosis-related markers. Additionally, the Basso, Beattie, Bresnahan locomotor rating scale, gait analysis, H&E staining, Nissl staining, TUNEL staining, and Annexin V/PI double staining were used to assess neurological function recovery and tissue damage repair. Results: After treatment with DL@ZIF-8@PF-127, the mitochondrial intrinsic apoptosis and ferroptosis pathways induced by SCI were significantly inhibited. The tissue structure damage, inflammatory cell infiltration, and neuronal loss at the injury site were markedly alleviated, accompanied by an increased number of Nissl bodies and reduced neuronal degeneration and gliosis. Conclusions: The DL@ZIF-8@PF-127 composite system can targetedly regulate the Nrf2/HO-1/P65 pathway through the synergistic effect of carrier materials and MSC-lysate. It inhibits ferroptosis and mitochondrial intrinsic apoptosis, alleviates inflammatory responses, improves mitochondrial function, and promotes neuronal repair, thereby mitigating spinal cord injury. This study provides a safe, convenient, and potential therapeutic strategy for SCI.