Taurine-loaded extracellular vesicles suppress mtDNA–cGAS–STING signaling by enhancing SIRT1-dependent mitophagy to alleviate neuronal senescence after spinal cord injury

Abstract

Spinal cord injury (SCI) triggers a cascade of secondary pathological processes that lead to progressive neuronal dysfunction and impaired functional recovery. Although cellular senescence has been increasingly implicated in neurodegenerative conditions, its role in SCI remains poorly defined. Here, we identify widespread senescence signatures in the injured spinal cord, with prominent enrichment in neurons, supporting neuronal senescence as a key pathological feature of SCI. To target this process, we developed a neuron-specific delivery system by encapsulating taurine within RVG-engineered extracellular vesicles, enabling efficient neuronal targeting. EV RVG -Taurine reduces neuronal senescence, attenuates neuroinflammation, and promotes axonal regeneration, resulting in improved functional recovery. Mechanistically, EV RVG -Taurine enhances SIRT1-dependent deacetylation of HSPA9 at lysine 409, thereby activating PINK1/Parkin-mediated mitophagy and facilitating the clearance of damaged mitochondria. This limits mitochondrial DNA (mtDNA) release and suppresses cGAS–STING signaling, leading to attenuation of senescence-associated secretory phenotype (SASP) signaling and disruption of the inflammation–senescence feedforward loop. Collectively, our findings identify neuronal senescence as a critical contributor of SCI pathology and support a SIRT1–HSPA9–mitophagy–mtDNA–cGAS–STING axis linking mitochondrial quality control to neuroinflammation. These results highlight a targeted EV-based taurine delivery strategy and support SIRT1-dependent mitophagy as a potential therapeutic target for SCI.