Abstract
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.
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Data availability
All data generated or analyzed during this study are included in this published article and its Supplementary Information. Source data are provided with this paper. The transcriptome sequencing data generated in this study have been deposited in the NCBI Sequence Read Archive under accession code PRJNA1390588 and its corresponding hyperlink: https://www.ncbi.nlm.nih.gov/sra/PRJNA1390588.
The metabolomic data of kidney and heart have been uploaded into the MetaboLights database (https://www.ebi.ac.uk/metabolights/) (Accession Number: MTBLS13988 (kidney)[https://www.ebi.ac.uk/metabolights/MTBLS13988], MTBLS13991(heart) [https://www.ebi.ac.uk/metabolights/MTBLS13991]). Source data are provided with this paper.
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Acknowledgements
This work was supported by the Young Top Talents Project of Shaanxi Sanqin Talents Special Support Program (2023STZZK09), the Fundamental Research Funds for the Central Universities (xzy012023002), the Shaanxi Fundamental Science Research Project for Chemistry & Biology (22JHQ072), the National Natural Science Foundation of China (82370726), Natural Science Foundation of Shaanxi Province (2024JC-YBMS-272), the Postdoctoral Science Foundation of Shaanxi Province (2023BSHYDZZ05), the Postdoctoral Fellowship Program of CPSF (GZC20232112). We appreciate the help from Kexin Sun (Laboratory Animal Center (LAC), Xi’an Jiaotong University, China) for assistance with echocardiographic measurement and renal doppler ultrasonography.
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Zhe Yang and Zhongmin Tian conceived the concept and directed the research. Xuechun Ren and Di Gao carried out material synthesis. Xuechun Ren, Di Gao, Rong Yun and Xinyang Liu performed material characterization and electrochemical tests. Xuechun Ren, Rong Yun, Chenna Di, Zeyu Hu and Xinyuan Zhang conducted the cell and animal experiments. Zhe Yang and Zhongmin Tian wrote the paper. All authors discussed the results and commented on the paper.
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Ren, X., Gao, D., Yun, R. et al. A urea-activated nanocarrier for site-specific SGLT2 inhibition and metabolic rescue against cardiovascular-kidney-metabolic syndrome. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71424-w
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DOI: https://doi.org/10.1038/s41467-026-71424-w
