A Glycan Key Unlocks Microglia Targeting and Reprogramming to Promote Functional Recovery After Spinal Cord Injury

Spinal cord injury (SCI) triggers uncontrolled neuroinflammation driven by dysfunctional microglia and pro-inflammatory-biased reprogramming, yet precise therapeutic strategies remain limited. Here, we report a novel glycan-targeted nanoparticle system (ICT@APD) designed to enhance the microglia-reprogramming potential of icaritin (ICT) while overcoming its inherent narrow therapeutic window. By functionalizing nanoparticles with 2,5-anhydro-D-mannitol (2,5-AM), a high-affinity ligand for the microglia-specific transporter GLUT5, ICT@APD achieves selective microglial uptake and amplifies the capacity of ICT to reprogram microglia toward an anti-inflammatory phenotype. The targeted reprogramming consequently creates a positive microenvironment that promotes axon regeneration, neuronal survival, and synaptic reconstruction, leading to significantly improved locomotor recovery after SCI. Our findings establish a novel glycan-mediated microglial targeting and reprogramming strategy for SCI repair, which may extend to other central nervous system disorders and provide a referenceable platform for the delivery of other therapeutic agents with a narrow therapeutic window.