Engineered nanoplex mediated targeted miRNA delivery to rescue dying podocytes in diabetic nephropathy

Abstract

MicroRNAs (miRNA) is vital for gene expression regulation and normal kidney function. Mainly, miRNA-30a is responsible for the homeostasis of podocytes. In the diabetic nephropathic condition, miRNA-30a is directly and primarily suppressed by hyperglycemic kidney induced Notch signaling pathway leads to podocyte damage and apoptosis. Thus, transferring the exogenous miRNA-30a to podocytes might improve albuminuria as well as podocytes injury. The deprived stability, poor targetability, and low specificity in vivo are critical limitations to attain this objective. This investigation reports the specific and efficient delivery of miRNA-30a mimic via cyclo(RGDfC)-gated polymeric-nanoplexes with dendrimer templates to alleviate podocyte conditions. The nanoplexes able to protect RNase enzyme and to exhibit greater cellular uptake viaαvβ3 receptor selective binding in HG treated podocytes. The nanoplexes up-regulated the expression level of miRNA-30a and repress the elevated Notch-1 signaling in HG exposed podocytes. The critical results of in vivo experimentation attribute marked suppression of Notch-1 in streptozotocin (STZ) induced diabetic C57BL/6 mice and reduced glomerular expansion and fibrosis in the glomerular area. Developed nanoplexes represents an efficient platform for the targeted delivery of exogenous miRNA to podocytes. The approach developed herein could be extrapolated to other gene therapeutics and other kidney-related diseases.