| Title: | 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 |
| Researcher: | Sarawut Lapmanee, Natchayaporn Thonapan, Siriwan Sriwong, Sakkarin Bhubhanil, Prapimpun Wongchitrat, Natthawut Charoenphon, Thitaphat Ngernsutivorakul, Khemmaphat Hooncharoen, Phichaporn Bunwatcharaphansakun, Mattaka Khongkow, Katawut Namdee |
| Degree: | Doctor of Medicine Program |
| Major: | Doctor of Medicine (M.D.) |
| Faculty of study: | Doctor of Medicine Program |
| Academic year: | 2569 (2026) |
| Published: | Biomedicine & Pharmacotherapy 2026, Vol. 201, 119724 https://doi.org/10.1016/j.biopha.2026.119724 |
Abstract
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 αvβ3-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..
Keywords: Alzheimer’s disease, Blood–brain barrier, Cannabidiol, Memory, RGD targeting