Urinary microenvironment-degradable nanocapsules for traceable therapy of diabetic nephropathy

Diabetic nephropathy (DN) is a serious complication of diabetes and a leading cause of end-stage renal disease. Current treatments using anti-inflammatory, antioxidant, and antifibrotic drugs are limited by rapid systemic clearance and poor renal retention. Here, we developed a urine-microenvironment responsive nanocapsule, MNP-THA@MnCaP, composed of a MnCaP nanoshell co-loaded with functionalized melanin (MNP) nanoparticles and thalidomide (THA) for synergistic therapy of DN. The nanocapsules preferentially accumulate in the kidneys via passive targeting and degrade under acidic urinary conditions, enabling controlled release of therapeutic agents. In vitro, MNP-THA@MnCaP alleviated oxidative stress, suppressed epithelial-mesenchymal transition, and reduced apoptosis in renal tubular cells. <i>In vivo</i>, the formulation targeted DN kidneys, attenuated oxidative injury, inflammation, and fibrosis, and restored renal function. Moreover, the released Mn²⁺ allowed T₁-weighted magnetic resonance imaging, while MNP supported photoacoustic imaging, facilitating real-time tracking of the treatment process. With excellent biocompatibility and biodegradability, MNP-THA@MnCaP represents a promising theranostic platform with strong translational potential for DN treatment.