An oral H2S nanotherapeutics for hypertensive chronic kidney disease via synergistic antihypertensive and renoprotective activities

Hypertensive chronic kidney disease (CKD) remains incurable, mainly because the current therapies are difficult to concurrently target elevated blood pressure and multifaceted renal abnormalities. Herein, we present an oral H 2 S nanomedicine, poly(lipoic acid trisulfide) (pLATS), with synergistic antihypertensive and renoprotective activities for treating hypertensive CKD. pLATS not only enables efficient oral delivery across multiple biological barriers via trisulfide exchange with thiols at mucosal, epithelial, and renal cellular interfaces, but also undergoes thiol-triggered intracellular depolymerization to achieve sustained release H 2 S and lipoic acid (LA)/LATS over 60 h, with H 2 S exerting multifactorial regulatory effects underlying hypertensive CKD. Meanwhile, LA/LATS upregulate H 2 S-producing enzymes, promoting sustained endogenous H 2 S biogenesis. In vivo, pLATS demonstrates markedly improved pharmacokinetics over its monomeric precursor, effectively lowering blood pressure, urine albumin-to-creatinine ratio, and plasma urea and creatinine by modulating genes in the renin-angiotensin system and endothelial function, surpassing the clinical antihypertensive losartan. In essence, this study pioneers a paradigm for comprehensive treatment of hypertensive CKD, with potential applications extending to broader chronic diseases.