Targeted delivery of the CB 2 receptor agonist JWH‐133 via VCAM‐1‐functionalised nanoparticles attenuates atherosclerosis and reveals sex‐specific therapeutic outcomes

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 (CB 2 ) 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 CB 2 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.