Multifunctional Cannabidiol-Loaded Nanoparticles Based on Herbal-Derived Bioactive Materials Provide Enhanced Neuroprotection against Ischemic Stroke

The ischemic cascade is central to the pathophysiology of ischemic stroke, making single-target strategies often inadequate. An ideal neuroprotective approach should therefore target multiple key components of the ischemic cascade. Herbal-derived bioactive materials offer dual "carrier and therapeutic" functions, providing unique advantages for addressing current treatment challenges. This study aims to develop a new multifunctional biomimetic nanoparticle using such herbal macromolecular materials. This nanoformulation (designated as CBDNPs) integrates polysaccharide for immunomodulation, apigenin for cardiovascular protection, and CBD for neuroprotection into a unified therapeutic strategy for the treatment of ischemic stroke. Biomimetic nanoparticles were produced with macrophage membrane (MM) coating on the surface of CBDNPs. MM/CBDNPs were characterized for physical properties and assessed for biological functions in vitro, with therapeutic efficacy evaluated in a middle cerebral artery occlusion (MCAO) model. The biomimetic CBD nanoformulation possessed favorable physicochemical properties and biological functions. Macrophage membranes can prevent drug-loaded nanoparticles and be engulfed by macrophages, and facilitate these nanoparticles to accumulate in the injured brain, while reducing ROS generation and stabilizing the mitochondrial membrane potential. In the MCAO rat model, administration of MM/CBDNPs reduced brain tissue damage and neuroinflammation and decreased neuronal apoptosis, exhibiting increased efficiency and neuroprotection. The underlying mechanism of anti-inflammation and neuroprotection of MM/CBDNPs was associated with the inhibition of NLRP3/NF-κB signaling pathway. These results demonstrate that MM/CBDNPs exhibited favorable neuroprotection and biocompatibility. This discovery offers new insights into the application of CBD and polymeric nanoparticles in the treatment of cerebral stroke.