Dual-responsive PDA-HP hydrogel enables mitochondria-targeted mild photothermal therapy for spinal cord repair.

Spinal cord injury (SCI) is a devastating neurological disorder with substantial economic and psychological burdens, underscoring the urgent need for effective therapeutic strategies. Here, we developed a dual-responsive hydrogel composed of polydopamine (PDA) and heparin-poloxamer (HP) that enables controllable mild photothermal stimulation under near-infrared (NIR) irradiation. The PDA-HP hydrogel exhibited excellent biocompatibility, biodegradability, and stable photothermal conversion. In a mouse SCI model, in situ administration of PDA-HP combined with NIR irradiation markedly improved locomotor recovery and mitigated tissue damage. Mechanistically, PDA-HP/NIR therapy reduced oxidative stress, preserved mitochondrial structure, restored ATP production, and-most notably-normalized the maladaptive overexpression of heat-shock protein 70 (HSP70) induced by SCI, thereby decreasing apoptosis and promoting neuronal survival. Quantitative proteomics further identified stress-chaperone and mitochondrial pathways as major targets of this intervention. To our knowledge, this is the first study demonstrating that PDA-HP-mediated mild photothermal modulation restores mitochondrial function through HSP70 normalization in SCI. These findings highlight a mitochondria-targeted mild photothermal strategy as a promising and clinically translatable approach for spinal cord repair.