An Inflammation-Responsive Hydrogel with Targeted Microglial Delivery of Eupatilin-Loaded Liposomes Orchestrates Immunomodulation for Spinal Cord Injury Repair

Abstract

Spinal cord injury (SCI) creates an inhibitory microenvironment that impedes neural regeneration. To overcome delivery barriers and achieve specific targeting of key inflammatory cells, we engineered an inflammation-responsive platform termed FlipE@GelMA/HAPBA (FGH), which integrates FTY720-functionalized eupatilin-loaded liposomes (FlipE) within a 3D-bioprinted fiber hydrogel composed of gelatin methacryloyl and phenylboronic acid-modified hyaluronic acid (GelMA/HAPBA). Under the acidic pH and elevated reactive oxygen species (ROS) conditions present at the SCI site, the hydrogel undergoes boronic ester cleavage, leading to controlled FlipE release. The surface-anchored FTY720 then guides FlipE to target microglia via TREM2 receptor targeting, facilitating eupatilin delivery to reprogram microglia from a pro-inflammatory M1 to an anti-inflammatory M2 phenotypes. In vitro, FGH exhibited inflammation-triggered release and preferential uptake by microglia. Conditioned media from FGH significantly downregulated M1 markers but upregulated M2 markers in microglial cultures, ultimately promoting neural stem cell proliferation and neuronal differentiation. In a rat T9 spinal cord complete transection model, FGH implantation enhanced M2 polarization at the lesion over 2–12 weeks, reduced scar formation, and stimulated axonal growth. Consequently, FGH-treated rats exhibited superior functional recovery.