Mo2Ti2C3/CeO2/Neurotrophin-3 MXene Hydrogel Combined with Electrical Stimulation Promotes Functional Recovery by Activating the Biogenesis and Fusion of Mitochondria in Spinal Cord Injury

Abstract

Traumatic spinal cord injury (SCI) initiates a pathological cascade dominated by mitochondrial dysfunction and unregulated oxidative stress, collectively generating an inhibitory lesion microenvironment that abrogates endogenous neural regenerative capacity. Herein, we fabricate a multifunctional conductive hydrogel scaffold by incorporating Mo2Ti2C3 MXene nanosheets, hollow CeO2 nanoparticles, and neurotrophin-3 (NT-3) within a crosslinkable matrix. When paired with exogenous electrical stimulation (ES), this combinatorial therapeutic platform synergistically activates two core mitochondrial regulatory cascades in injured neurons: the PGC-1α/NRF1/TFAM axis governing mitochondrial biogenesis, and Mfn2/OPA1 signaling mediating mitochondrial fusion. Comprehensive in vitro characterizations validate the hydrogel’s favorable long-term cytocompatibility, robust reactive oxygen species (ROS) scavenging activity, tunable biodegradation kinetics, and sustained NT-3 delivery; together, these properties effectively restrain intracellular ROS overproduction and stabilize mitochondrial structural and metabolic homeostasis. In a mouse contusion SCI model, local implantation of the Mo2Ti2C3/CeO2/NT-3 hydrogel combined with intermittent electrical stimulation substantially alleviates secondary tissue damage by shrinking lesion cyst volume and attenuating glial scarring, which in turn promotes pronounced axonal sprouting and restores hindlimb locomotor function. By merging conductive biomaterial bridging with targeted mitochondrial homeostatic modulation, this work establishes a dual-modal therapeutic strategy with great translational potential for neural tissue engineering and post-SCI regenerative repair.