A novel treatment for diabetic nephropathy: Folate receptor-targeted delivery of TLR4 siRNA via functionalized PLGA nanoparticles in streptozotocin-induced diabetic murine models

Diabetic kidney disease (DKD), a prominent microvascular complication of diabetes mellitus and the leading cause of end-stage renal disease (ESRD), was addressed through a novel nanotherapeutic approach. This study engineered folic acid-conjugated poly(lactic-co-glycolic acid) nanoparticles (FA-PLGA NPs) for the folate receptor (FR)-targeted delivery of Toll-like receptor 4 small interfering RNA (TLR4 siRNA) to treat diabetic nephropathy (DN). In a streptozotocin-induced DN murine model, administration of FA-PLGA NPs/TLR4 siRNA significantly mitigated renal injury compared to untreated DN controls. This was evidenced by reduced mesangial matrix expansion, downregulation of TLR4/CD86/FLOR2 expression, decreased urinary protein excretion, and lowered circulating IL-6 and TNF-α levels. Importantly, renal function parameters, including urea nitrogen, serum creatinine, and albumin) were restored to near-normal levels. These results demonstrate that FRβ-targeted TLR4 siRNA delivery via FA-PLGA NPs effectively reduces inflammation and renal damage, establishing a promising novel therapeutic strategy for DN.