Targeted CB2 drug delivery reduced mouse plaque deposits, with sex differences

BACKGROUND AND PURPOSE: Atherosclerosis, a chronic inflammatory disease characterised by lipid accumulation and endothelial dysfunction, remains a leading cause of cardiovascular morbidity and mortality. While cannabinoid 2 (CB2) receptor agonists show therapeutic promise in preclinical studies, their systemic application is hindered by poor bioavailability and off-target effects. Consequently, targeted delivery systems are essential to enhance therapeutic efficacy and mitigate adverse effects. EXPERIMENTAL APPROACH: This study presents a targeted nanotherapeutic strategy for localising the CB2 receptor agonist directly at atherosclerotic lesions. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), encapsulating the selective agonist JWH-133 and functionalised with a VCAM-1 binding peptide (VBP) for selective binding to vascular cell adhesion molecule-1 (VCAM-1) (VBP-JWH-133-NPs), were developed. In vivo experiments were conducted in both male and female apolipoprotein E-deficient (ApoE-/-) mice to assess the anti-inflammatory and lipid-modulating effects of the nanotherapy. Serum lipid profiles, aortic plaque burden and key inflammatory markers were analysed. KEY RESULTS: VBP-JWH-133-NPs significantly reduced foam cell-rich depositions and modulate systemic inflammatory markers in both sexes, demonstrating superior anti-atherogenic efficacy compared with free JWH-133. The therapeutic benefits are notably more pronounced in male mice, which exhibit greater initial plaque area and lipid deposition. CONCLUSION AND IMPLICATIONS: These findings underscore the potential of VBP-JWH-133-NPs as an efficient and superior delivery system for cannabinoid therapies in atherosclerosis. By addressing sex as a biological variable, this approach offers a nuanced strategy for developing more effective and precise cardiovascular interventions.