Oxidative stress plays a central role in the pathogenesis of cardiovascular and metabolic diseases, contributing to endothelial dysfunction, inflammation, and progression of tissue damage [1,2]. Advances in nanomedicine have opened new possibilities for targeted drug delivery, offering potential to enhance therapeutic efficacy while minimizing systemic side effects [3,4].

This study aimed to investigate the cardiovascular and metabolic effects of aliskiren and simvastatin delivered via biodegradable polymeric nanoparticles in experimental models of hypertension and metabolic syndrome, with a focus on modulation of oxidative stress and nitric oxide (NO) signaling.

Spontaneously hypertensive rats (SHR) and obese Zucker rats with metabolic syndrome were used as experimental models. Aliskiren-loaded poly(lactic acid) (PLA) nanoparticles (25 mg/kg/day) were administered to SHR for 3 weeks, and simvastatin-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (15 mg/kg/day) were given to obese rats for 6 weeks. Blood pressure was measured weekly. Nanoparticle distribution was assessed using confocal microscopy. Plasma lipid profiles and tissue levels of conjugated dienes were analyzed. In cardiac tissue, gene expression of (pro)renin receptor (Atp6ap2), angiotensin II receptor (Agtr1), and angiotensin-converting enzyme (ACE) was quantified. Nitric oxide synthase (NOS) activity and the protein expression of Akt, endothelial NOS (eNOS), phosphorylated eNOS (p-eNOS), neuronal NOS (nNOS), NADPH oxidase, and NF-κB were evaluated in the heart and aorta.

Aliskiren-loaded nanoparticles significantly reduced blood pressure in SHR, downregulated Atp6ap2 and ACE gene expression, and increased cardiac NOS activity. These changes were associated with decreased expression of NADPH oxidase and reduced lipid peroxidation markers, indicating a reduction in oxidative stress. Simvastatin-loaded nanoparticles decreased plasma LDL-cholesterol levels and, when co-administered with coenzyme Q10, further increased NOS activity and the expression of Akt, eNOS, and p-eNOS in both heart and aorta. Both nanoparticle formulations downregulated NF-κB and NADPH oxidase, confirming their anti-inflammatory and antioxidant potential. In conclusion, these results suggest that targeted delivery of cardiovascular drugs via nanoparticles may effectively modulate ROS/NO balance and improve cardiometabolic outcomes.