MMP-responsive nanodrug loaded with glibenclamide for targeted repair of acute spinal cord injury

• Gliben@PEG-PCL-ACPP targets the spinal cord injury site with sustained release. • Better blood spinal cord barrier penetration ability. • Low hypoglycemia risk and enhanced anti-inflammatory and neuroprotective effects. • Inhibit progressive hemorrhagic necrosis in the spinal cord injury. • Gliben@PEG-PCL-ACPP can inhibit Sur-1 expression and p38/MAPK phosphorylation. Spinal cord injury (SCI) is a severe traumatic neurological disease characterized by quadriplegia and paraplegia, leading to high rates of disability and mortality. The treatment of SCI remains a tremendous challenge due to limited medicine distribution to the lesion site and difficulty in permeating the blood-spinal cord barrier (BSCB). To overcome these issues, a novel polymer-based nanodrug delivery system was developed. After SCI, the matrix metalloproteinases (MMPs) increase rapidly around the injured site. By incorporating activated cell-penetrating peptides (ACPP), which specifically target MMP-2 and MMP-9 into the polyethylene glycol-polycaprolactone (PEG-PCL), a nano delivery system PEG-PCL-ACPP was created. Glibenclamide, a widely employed hypoglycemic drug, has been recognized for its ability to mitigate secondary injury in SCI. In this study, it was encapsulated within the PEG-PCL-ACPP to achieve targeted delivery and sustained release in the affected area. The therapeutic effects and mechanisms of Gliben@PEG-PCL-ACPP were investigated through both in vitro and in vivo experiments. These experiments verified that Gliben@PEG-PCL-ACPP exhibited favorable biocompatibility and its successful targeting of the affected region. Furthermore, it not only significantly reduced the progressive hemorrhagic necrosis (PHN), but also demonstrated anti-inflammatory and neuroprotective effects. Consequently, Gliben@PEG-PCL-ACPP has great potential for clinical application in SCI treatment.