In Situ Forming ROS-Scavenging Hydrogel with a STING Inhibitor Improves Recovery After Acute Spinal Cord Injury by Modulating Inflammatory Microenvironment.

Abstract

The inflammatory cascade initiated by acute spinal cord injury (SCI) is a crucial element contributing to subsequent pathological damage. Uncontrolled or excessive inflammatory responses aggravate neural tissue destruction and hinder the regenerative process. Stimulator of interferons genes (STING) is a key regulator in the innate immune signaling pathway that promotes the generation of inflammatory mediators by activating the TBK1 and IRF3 signaling pathways, thereby shaping the post-injury microenvironment. In this study, we developed a hyaluronic acid-phenylboronic acid-polyvinyl alcohol-based hydrogel (HA-PBA-PVA, termed HPP) as a local delivery vehicle for the STING-specific inhibitor C-176, which was applied directly to the injury epicenter in a rat model of complete spinal cord transection. The locally implanted C-176@HPP can effectively deliver C-176 to the injured site, markedly reducing the expression of pro-inflammatory cytokines by regulating the STING/TBK1 signaling pathway. Moreover, the administration of C-176@HPP can significantly attenuate microglial activation and promote neuronal survival and axonal regeneration, which eventually contribute to locomotor improvement after SCI. Our findings demonstrate that C-176@HPP provides a promising strategy for ameliorating neuro-inflammation and facilitating neural tissue regeneration after SCI.