Neutrophil-Hitchhiking and Microenvironment-Responsive Cascade Nanoparticles for STING Inhibition and Spinal Cord Injury Repair.

Abstract

Excessive acute inflammation following spinal cord injury (SCI) is a primary driver of secondary neuronal damage, with early neutrophil infiltration playing a critical, deleterious role. Clinical evidence linking high neutrophil counts to SCI severity underscores the need for precision immunomodulation. Herein, we report T-H151, a smart, bio-responsive nanoplatform designed to suppress neuroinflammation and enhance functional recovery via selective inhibition of the STING signaling pathway. T-H151 consists of a liposomal carrier encapsulating the STING inhibitor H151, surface-functionalized with a modular peptide design: a neutrophil elastase-binding peptide (NEBP) for active hitchhiking, an MMP9-responsive linker for site-specific activation, and a neuron-targeting peptide (TET) for enhanced cellular uptake. This architecture facilitates efficient neutrophil-mediated transport to the lesion site, followed by MMP9-triggered, precision release of H151 within the neuronal microenvironment. In SCI mouse models, T-H151 significantly improves motor function and preserves blood-spinal cord barrier integrity. Mechanistically, T-H151 suppresses the STING axis, inhibits microglial/macrophage activation, and reduces pro-inflammatory cytokines (IL-1β, TNF-α). Transcriptomic analysis further confirms a profound downregulation of the NF-κB and JAK-STAT inflammatory pathways. Collectively, this targeted nanoplatform offers a transformative, bio-responsive strategy for mitigating neuroinflammation and promoting therapeutic outcomes in spinal cord repair.