REN and chronic kidney disease: Our key contributions are summarized as follows: (1) we developed STS-loaded PEG-PLA-CPLA/F127 NPs that extend STS release for up to 7 days; (2) weekly STS-loaded NP treatment reduced systolic and diastolic BP by 10 mm Hg and 8 mm Hg, respectively, in juvenile CKD rats; (3) the protective effect of STS-loaded NPs is linked to increased renal expression of CSE and DAO; (4) CKD disrupts the NO signaling pathway, whereas STS-loaded NP therapy enhances NO bioavailability; and (5) the beneficial effects of STS-loaded NPs were associated with decreased levels of renin and ACE1.