Bioengineered exosome-mRNA hybrids: a breakthrough in targeted miRNA delivery for diabetic kidney fibrosis therapy.

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.