Curcumin-Loaded Gelatin Nanoparticles Cross the Blood-Brain Barrier to Treat Ischemic Stroke by Attenuating Oxidative Stress and Neuroinflammation.

Background: Ischemic stroke is a medical emergency for which effective treatment remains inadequate. Curcumin (Cur) is a natural polyphenolic compound that is regarded as a potent neuroprotective agent. Compared to synthetic pharmaceuticals, Cur possesses minimal side effects and exhibits multiple mechanisms of action, offering significant advantages in the treatment of ischemic stroke. However, drawbacks such as poor water solubility and transmembrane permeability limit the efficacy of Cur. In recent years, nano-delivery systems have attracted great interest in the field of stroke therapy as an effective method to improve drug solubility and cross the blood-brain barrier (BBB). Methods: In this study, a novel nanomedicine (Cur@GAR NPs) for ischemic stroke treatment was developed based on Cur-loaded gelatin nanoparticles (Cur@Gel NPs) that were then functionalized and modified with rabies virus glycoprotein (RVG29) to target brain tissue. The stability, antimicrobial properties, antioxidant properties, neuroprotective effects, neuronal cell uptake, and biocompatibility of Cur@GAR NPs were investigated in vitro. The in vivo therapeutic effect of Cur@GAR NPs on ischemic stroke was investigated in a middle cerebral artery occlusion (MCAO) rat model using the Morris water maze test and the open field test, and the potential mechanism of action was further investigated by histological analysis. Results: The resulting Cur@GAR NPs improved the solubility of Cur and exhibited good dispersion. In vitro studies have shown that Cur@GAR NPs exhibit great antimicrobial properties, antioxidant properties and intracellular reactive oxygen species (ROS) protection. Notably, RVG29 significantly enhanced the uptake of Cur@GAR NPs by SH-SY5Y cells. Furthermore, in vivo studies verified the role of Cur@GAR NPs in reducing nerve damage and supporting neurological recovery. In the MCAO rat model, Cur@GAR NPs significantly attenuated neuroinflammation, reduced neuronal apoptosis and restored behavioral functions to a great extent. Conclusion: Together these findings implied that Cur@GAR NPs could provide a novel and promising approach for effective ischemic stroke treatment.