Modified Zn-MOF multifunctional nanoparticles for combination therapy of DN and exploratory study of the nephroprotective effect

The critical pathogenic factors in the initiation and progression of diabetic nephropathy (DN) include hyperglycemia, oxidative stress, and inflammatory responses. Current therapeutic interventions for DN remain constrained by the intricate pathophysiological mechanisms that are involved in the dysregulations of multiple renal signaling pathways. Zinc (Zn) is an essential trace element that participates in diverse physiological processes, exhibits protective effects against oxidative stress-induced apoptosis, and plays a pivotal role in insulin biosynthesis and secretion. In our exploratory study, we aimed to develop targeted intervention in diabetes-associated DN pathogenesis by engineering metformin (MET)-encapsulated Zn-MOF nanoparticles conjugated with a renal-targeting protein (KTP-Zn-MOF/MET). In vivo imaging analyses revealed that renal accumulation of these multifunctional nanoparticles was significantly enhanced in BALB/c nude mice. The nephroprotective efficacy was preliminary explored in a rat model with renal injury induced using streptozotocin. Intravenous administration of KTP-Zn-MOF/MET ameliorated multiple DN-related pathological manifestations, including renal functional impairment, cellular apoptosis, lipid peroxidation, and oxidative stress. Our findings indicated that KTP-Zn-MOF/MET is a novel therapeutic strategy for precise renal targeting and multi-target intervention in DN management, with significant potential for clinical translation.