ROS-responsive hydrogel delivering liposomal indole-3-propionic acid promotes spinal cord injury repair by enhancing CX3CL1-CX3CR1 mediated neuron-microglia communication

Abstract

Spinal cord injury (SCI) is a devastating neurological disorder characterized by excessive neuroinflammation and limited regenerative capacity. Here, we developed a reactive oxygen species (ROS)-responsive hydrogel for localized delivery of liposomal indole-3-propionic acid (IPA), a gut microbiota-derived metabolite with neuroprotective potential. The hydrogel exhibited favorable injectability, self-healing capability, and ROS-responsive degradation, enabling sustained release and prolonged retention of IPA at the lesion site. In vitro, IPA-loaded liposomes effectively attenuated lipopolysaccharide-induced inflammation and promoted axonal regeneration with favorable biosafety. In the rat SCI model, localized delivery of liposomal IPA significantly improved locomotor recovery, electrophysiological function, and tissue preservation while reducing cavity formation and secondary injury. Moreover, IPA promoted neuronal survival, enhanced axonal integrity, and shifted microglia toward a pro-repair phenotype. Single-nucleus RNA sequencing identified enhanced CX3CL1-CX3CR1 mediated neuron-microglia communication following IPA treatment, accompanied by enrichment of PI3K/AKT signaling pathway in both neurons and microglia. In addition, IPA facilitated microglial migration toward the lesion core, suggesting coordinated modulation of the neuroinflammatory microenvironment after SCI. Collectively, our study identifies a previously unrecognized therapeutic role of IPA in spinal cord repair and presents a ROS-responsive nanoplatform for localized metabolite delivery to regulate neuron-microglia crosstalk and promote functional recovery after SCI.