A urea-activated nanocarrier for site-specific SGLT2 inhibition and metabolic rescue against cardiovascular-kidney-metabolic syndrome

Cardiovascular-kidney-metabolic (CKM) syndrome, driven by interlinked metabolic, renal and cardiovascular dysfunction, remains therapeutically challenging due to its multi-organ complexity. Although sodium-glucose cotransporter 2 (SGLT2) inhibitors such as empagliflozin (EMPA) confer cardiorenal benefits, their efficacy is limited by poor renal specificity and systemic off-target exposure. Here, we report a kidney-targeted and urea-responsive nanocarrier (T-PAAD NPs) that enables renal tubule-selective release of EMPA in response to pathological urea concentrations. This delivery strategy, rarely explored in nanomedicine, synergistically enhances therapeutic precision while integrating reactive oxygen species (ROS) scavenging to mitigate oxidative stress. In male mouse models of CKM, T-PAAD NPs/EMPA effectively reprogram cardiac and renal energy metabolism, restore filtration and contractile function, and achieve superior glycemic, renal, and cardiovascular outcomes compared to free EMPA. By coupling bioresponsive controlled release with metabolic modulation, this nanoplatform provides a promising approach to treat CKM and other systemic metabolic disorders. Due to interacting metabolic, renal and cardiovascular dysfunction, cardiovascular-kidney-metabolic syndrome is difficult to treat. Here, the authors show a urea-responsive, kidney-targeted nanocarrier enables site-specific SGLT2 inhibition, restores cardiorenal metabolism and improves efficacy.