Ultrasmall Cu2−xSe nanoparticles alleviate vascular calcification through inhibiting oxidative stress and NF-κB/NLRP3-mediated inflammation

Vascular calcification, prevalent in patients with chronic kidney disease, atherosclerosis, and diabetes, is strongly associated with elevated cardiovascular morbidity and mortality, highlighting the urgent need for effective treatments. Oxidative stress is a key contributor to the progression of vascular calcification. Nanozymes, nanomaterials with enzyme-like catalytic properties, exhibit strong reactive oxygen species (ROS) scavenging abilities and good biocompatibility, making them promising therapeutic candidates. This study aims to investigate whether polyvinylpyrrolidone (PVP)-functionalized ultrasmall Cu_2-xSe nanoparticles (CSP NPs) act as nanozymes for treating vascular calcification. In vitro, CSP NPs significantly inhibit calcification of rat and human vascular smooth muscle cells (VSMCs) and reduce the expression of osteogenic markers Runx2 and BMP2. Moreover, CSP NPs alleviate calcification of rat and human arterial rings. In a mouse model, CSP NPs localize to certain areas, such as the aortic arch and abdominal aortas, and are safely metabolized by the liver and kidneys without organ toxicity. Further analyses confirm that CSP NPs inhibit mouse and chronic kidney disease (CKD) rat aortic calcification. Mechanistically, CSP NPs inhibit oxidative stress and mitochondrial dysfunction. Additionally, CSP NPs decrease the expression of NF-κB and NLRP3, thus reducing the levels of inflammatory cytokines IL-1β and IL-6. CSP NPs suppress NLRP3 activator-induced calcification in VSMCs and arterial rings. This study provides the first evidence that CSP NPs alleviate vascular calcification by inhibiting oxidative stress and NF-κB/NLRP3-mediated inflammation, suggesting a promising therapeutic approach.