Introduction Diabetic nephropathy (DN) is characterized by progressive podocyte injury, yet actionable upstream regulators and precise targeted delivery strategies remain limited. This study investigated the role of poly (ADP-ribose) polymerase 1 (PARP1) in hyperglycemia-induced podocyte damage and developed a biomimetic targeted siRNA delivery system to silence PARP1. Methods Transcriptomic profiling was performed in MPC5 podocytes exposed to high glucose. Functional validation was conducted using the PARP1 inhibitor PJ-34 and PARP1 gene silencing in vitro and in a streptozotocin-induced type 1 diabetic mouse model. A PLGA-core nanoparticle system loaded with PARP1 siRNA and coated with red blood cell membrane (RBCm), further functionalized with the podocyte-targeting ligand BMS-α, was engineered and evaluated for targeting efficiency and therapeutic efficacy. Results PARP1 was significantly upregulated under high-glucose conditions and associated with activation of the TGFβ/Smads signaling pathway. Pharmacological inhibition and gene silencing of PARP1 attenuated pathway activation, restored autophagic flux, and reduced apoptosis, inflammation, and profibrotic responses in vitro , while alleviating glomerular injury in diabetic mice. The siPARP1-NPs@RBCm-BMS-α system demonstrated favorable physicochemical stability, effective siRNA encapsulation, enhanced podocyte targeting, and improved renal structure and function in vivo . Discussion These findings identify PARP1 as a key regulator of podocyte injury in DN via the TGFβ/Smads pathway and support the biomimetic receptor-relevant siRNA platform as a promising targeted therapeutic strategy for diabetic nephropathy.
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