Enhanced glomerular transfection by BMP7 gene nanocarriers inhibits CKD and promotes SOX9-dependent tubule regeneration

Abstract

Renal fibrosis and loss of kidney function are key characteristics of chronic kidney disease (CKD). To address the lack of effective treatments, multifunctional layer-by-layer (LbL) assembled polymeric gene-carrier nanoparticles (PCHS-NP) are prepared to realize preferential accumulation and retention within renal glomerular cells, thereby effectively leveraging cortically localized structures for the synthesis and paracrine secretion of the antifibrotic growth factor, bone morphogenetic protein-7 (BMP7). PCHS-NP had stable homogenous morphologies, kidney-targeting functionality, antioxidative effects, and high transfection efficiency. In unilateral ureteral obstruction (UUO)-induced renal fibrosis, a single systemic injection of PCHS-NP prevents tubular atrophy and interstitial fibrosis, and the resultant tissue microenvironment is more conducive to tubular regeneration driven by the upregulation of proliferative SOX9-expressing tubular cells. In longer-term folic acid (FA)-induced renal fibrosis, we show that early, late, and repeat systemic injections restore kidney health and function. This study indicates that PCHS-NP accomplish a promising therapeutic option for the treatment of CKD.