A Synergistic Semaglutide-targeted Fluorescent Nanodrug Delivery System and its Therapeutic Efficacy in Diabetic Nephropathy Treatment

Diabetic nephropathy (DN) is a common, debilitating complication of diabetes and a primary cause of end-stage renal disease (ESRD), characterized by high incidence and progressive renal impairment. Podocyte injury is a pivotal factor in DN progression, with podocyte depletion closely linked to glomerular pathology, proteinuria, and renal function decline. In this study, we introduce a novel compound, compound 1, which has demonstrated significant synergy with Semaglutide, a standard DN therapy. Compound 1 was precisely characterized using single-crystal X-ray diffraction to confirm its unique structural attributes. To overcome limitations in solubility and biocompatibility, we developed an advanced targeted nanocarrier, CP1, a metal-organic framework (MOF) engineered to co-deliver compound 1 and Semaglutide, enhancing the combined therapeutic effects for DN treatment. For further improvements in biocompatibility and reduced toxicity, CP1@1@Semaglutide was encapsulated within a chitosan (CS) and polyethylene glycol (PEG) shell, forming the CS-PEG@CP1@1@Semaglutide composite. This composite integrates the efficient drug delivery capacity of chitosan, the hydrophilic linkage of PEG, and the robust stability of the CP1 framework, enhancing targeting precision and therapeutic efficacy. Evaluations of podocyte viability and apoptosis regulation in injury models confirm that CS-PEG@CP1@1@Semaglutide effectively mitigates podocyte damage, providing new insights into DN therapy and highlighting the therapeutic promise of the newly synthesized compound 1.