Photothermally Tunable Nano‐Fusogen Enables Spatiotemporally Controlled Membrane Resealing after Traumatic Spinal Cord Injury

ABSTRACT Rapid restoration of membrane integrity represents a potential therapeutic approach to rescuing cells after traumatic spinal cord injury (TSCI). In contrast to endogenous repair mechanisms, which are often insufficient under severe injury conditions, synthetic membrane‐resealing materials offer substantial potential but remain constrained by limited control over membrane interactions and functional activation. Here, we show that mild hyperthermia markedly enhances the membrane‐resealing efficacy of polyethylene glycol (PEG), which may be associated with increased lipid bilayer fluidity and Annexin A1 expression. Based on these findings, we engineer a photothermal nano‐fusogen by conjugating PEG and cholesterol‐modified PEG onto gold nanorods, enabling targeted membrane insertion in vivo followed by near‐infrared–triggered localized heating to achieve efficient membrane repair. In a rat TSCI model, a single intraspinal administration of the nano‐fusogen combined with irradiation restores spinal cord compound action potentials, reduces lactate dehydrogenase release, suppresses cleaved caspase‐3 expression, and was accompanied by higher expression of selected membrane‐repair‐associated genes. Longitudinal analyses further demonstrate improved hindlimb locomotor recovery and enhanced neuronal survival. This work establishes a photothermally tunable nano‐fusogen platform for spatiotemporally controlled membrane repair and functional recovery after TSCI, with broader implications for acute injuries characterized by catastrophic membrane disruption.