Matrix Metalloproteinase-Activatable Nanodrug Crossing Blood–Spinal Cord Barrier for On-Demand Drug Release in Spinal Cord Injury Repair

Methylprednisolone (MPS) has demonstrated considerable merits in the clinical treatment of spinal cord injury (SCI), yet its application is conspicuously constrained by the narrow therapeutic time window and grave side effects, such as gastrointestinal bleeding. Furthermore, the impediment posed by the blood-spinal cord barrier (BSCB) hinders the effective delivery of drugs to the injured tissue. In this study, we developed a nanodrug that exhibited programmed responsiveness to matrix metalloproteinases (MMPs) and reactive oxygen species (ROS). The surface peptide of the neutrally charged nanodrug was precisely tailored to be cleaved by MMPs at the SCI site, converting it to a robustly cationic entity, which facilitated efficient penetration of the BSCB. Subsequently, the encapsulated drugs underwent a swift release process within the SCI microenvironment, characterized by heightened ROS expression. The results showed that an impressive 7.42% of intravenously administered nanodrugs were successfully targeted to the lesion site, which inhibited cell apoptosis and fostered the survival of damaged neurons while concurrently mitigating the side effects compared to unmodified drugs. Besides, our investigation uncovered that MPS possessed the capability to modulate the polarization of macrophages, regulating the production of proinflammatory and anti-inflammatory cytokines, ultimately culminating in the restoration of motor function in injured mice. In essence, this ingeniously crafted nanodrug offers invaluable insights and guidance for the clinical management of SCI.