Astrocyte-derived exosome-mediated siRNA delivery combined with quercetin-Mn complex promotes neural repair in spinal cord injury.

Neuroinflammation and oxidative stress are pivotal drivers of neurological dysfunction following spinal cord injury (SCI). Consequently, precise modulation of pathological glial cells and amelioration of the neuronal microenvironment represent a promising therapeutic strategy. Herein, we developed an injectable, self-healing hydrogel system composed of oxidized sodium alginate, carboxymethyl chitosan, and tannic acid (OCT) for the sustained co-delivery of a Quercetin-Manganese complex (QM) and astrocyte-derived extracellular vesicles encapsulating siRNA (AEVs@siRNA). RNA sequencing revealed significant enrichment of the TNF and chemokine signaling pathways in SCI mice, with a notable upregulation of Serpina3n. This gene, predominantly expressed in astrocytes, modulates their reactive polarization. Leveraging the innate tropism of astrocyte-derived extracellular vesicles, we achieved targeted delivery of Serpina3n-targeting siRNA to astrocytes at the lesion site. This approach effectively suppressed the expression of Serpina3n, inhibiting the transition to a neurotoxic A1 phenotype and alleviating neuronal damage. Concurrently, the sustained release of QM NPs potently scavenged reactive oxygen species, significantly mitigating neuronal ferroptosis. Further mechanistic investigations demonstrated that this combinatorial system attenuated neuroinflammation by inhibiting NF-κB p65 signaling to reduce A1 astrocyte activation, and protected neurons by regulating the SLC7A11/GPX4 axis to counteract apoptosis and ferroptosis, both in vitro and in vivo. Consequently, this targeted delivery system represents a promising approach for enhancing therapeutic efficacy and promoting neural repair following SCI.