Targeting Delivery of Cyanidin‐Loaded With Ti 3 C 2 Nanosheets for Alleviating Vascular Calcification in Chronic Kidney Disease

ABSTRACT Vascular calcification is highly associated with cardiovascular morbidity and mortality among patients with chronic kidney disease (CKD). Despite its clinical severity, no effective therapies exist to halt its progression. Sirtuin 6 (SIRT6) has recently emerged as a promising therapeutic target for vascular calcification. Our prior work demonstrated that SIRT6 activation inhibits vascular calcification by attenuating the osteogenic trans differentiation of vascular smooth muscle cells (VSMCs). While the natural compound cyanidin can activate SIRT6, its clinical translation is hampered by poor bioavailability and the absence of targeted delivery systems. To address this, we developed a dual targeting nanoplatform (TROC) based on Ti₃C₂ nanosheets co‐assembled with osteocalcin (OCN) and RANKL antibodies for the targeted delivery of cyanidin. Leveraging data from the Framingham Heart Study offspring cohort and in vitro VSMC models, we first established dietary anthocyanins as an independent protective factor against aortic calcification. We then demonstrated that TROC exhibits excellent stability and dose‐dependently reduces calcium deposition in VSMCs. Furthermore, in vivo fluorescence and computed tomography (CT) multimodal imaging confirmed the selective accumulation of TROC at calcification sites and its efficacy in alleviating vascular calcification. This novel drug delivery system represents a promising strategy for advancing the clinical treatment of Vascular calcification.