RGD-functionalized cannabidiol lipid nanoparticles improve brain delivery and alleviate cognitive and metabolic dysfunction via gut-brain axis modulation in an Alzheimer's disease model

Abstarct Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuronal loss. Evidence links gut–brain axis dysfunction and metabolic disturbances to AD. Although cannabidiol (CBD) has neuroprotective effects, its use is limited by poor bioavailability and brain delivery. Methods Arginylglycylaspartic acid (RGD)-functionalized, CBD-loaded lipid nanoparticles (CBD/LNP-RGD) were developed to enhance targeted delivery across the blood–brain barrier (BBB) via integrin α v β 3 -mediated transcytosis. Cellular uptake and BBB permeability were evaluated in vitro . Anti-inflammatory and antioxidant effects were assessed in Aβ/LPS-induced models. In vivo efficacy was examined using cognitive-behavioral tests, including the novel object recognition and the Morris water maze. Metabolic parameters, histopathology, synaptic protein expression, and gut barrier integrity were also evaluated. Results CBD/LNP-RGD demonstrated a 3-fold increase in cellular uptake and a 65% enhancement in BBB transport compared to non-targeted formulations. Treatment significantly reduced pro-inflammatory cytokines (i.e., IL-6 and TNF-α, p < 0.001) and intracellular reactive oxygen species ( p < 0.001). In vivo , CBD/LNP-RGD improved cognitive performance comparable to Donepezil ( p < 0.001). Additionally, it normalized glycemic control, insulin resistance, and triglyceride levels without hepatic or renal toxicity. At the tissue level, CBD/LNP-RGD reduced Aβ and tau pathology, restored short-chain fatty acids, preserved hippocampal neuronal integrity, and upregulated synaptophysin and PSD-95 proteins. Enhanced intestinal barrier function was evidenced by increased expression of tight junction proteins ZO-1 and occludin. Conclusions CBD/LNP-RGD represents a multifunctional nanotherapeutic platform that improves brain delivery and exerts neuroprotective, anti-inflammatory, antioxidant, and metabolic regulatory effects. Its ability to modulate both central pathology and the gut–brain axis highlights its potential as a disease-modifying strategy for Alzheimer’s disease.