A BSCB‐Penetrating Nanoplatform for Enhanced Luteolin Delivery in PRMT2‐Targeted Epigenetic Therapy of Spinal Cord Injury

Abstract

ABSTRACT Spinal cord injury (SCI) is a devastating disorder of the central nervous system (CNS) leading to irreversible neurological deficits. Effective pharmacotherapy remains elusive, due to the restrictive blood‐spinal cord barrier (BSCB), underscoring the urgent need for targeted and efficient drug delivery strategies. Luteolin (LUT), a natural flavonoid with potent anti‐neuroinflammatory properties, presents a promising therapeutic option; however, it is compromised by poor solubility, low bioavailability, and limited BSCB penetration. Drawing inspiration from the traditional Chinese medicine concept of the “orifice‐opening” effect of borneol (BO), we developed BO‐modified mesoporous silica nanoparticles (MSN‐BO@LUT) for targeted LUT delivery to the spinal cord. MSN‐BO@LUT significantly enhanced LUT delivery to the spinal cord, achieving a 286.36‐fold increase over LUT, and maintained a concentration of 802.17 ng/mL at 24 h. MSN‐BO@LUT demonstrated robust anti‐neuroinflammatory and neuroprotective effects in SCI mice, reducing microglial infiltration, promoting functional recovery, and showing favorable efficacy and safety compared with the positive control methylprednisolone. Mechanistically, released LUT targets protein arginine N‐methyltransferase, reduces toll‐like receptor 4 methylation, and inhibits nuclear factor kappa B‐mediated pro‐inflammatory signaling, thereby suppressing microglial M1 polarization. These findings suggest that MSN‐BO@LUT not only provides a developed, safe, effective nanotherapeutic strategy for SCI treatment but also serves as a translatable template for developing precision nanomedicines targeting CNS disorders.