Dual-Regulated Functionalized Liposome-Nanoparticle Hybrids Loaded with Dexamethasone/TGFβ1-siRNA for Targeted Therapy of Glomerulonephritis.

Abstract

Mesangial cell (MC)-mediated glomerulonephritis is a frequent cause of end-stage renal disease, with immune inflammatory damage and fibrosis as its basic pathological processes. However, the treatment of glomerulonephritis remains challenging owing to limited drug accumulation and serious side effects. Hence, the specific codelivery of "anti-inflammatory/antifibrosis" drugs to the glomerular MC region is expected to yield better therapeutic effects. In this study, liposome-nanoparticle hybrids (Au-LNHy) were formed by coating the surface of gold nanoparticles with a phospholipid bilayer; the Au-LNHys formed were comodified with PEG and α8 integrin antibodies to obtain gold nanoparticle immunoliposomes (Au-ILs). Next, the Au-ILs were loaded with dexamethasone and TGFβ1 siRNA to obtain DXMS/siRNA@Au-ILs. Our results showed that the functionalized nanoparticles had a core-shell structure, a uniform and suitable particle size, low cytotoxicity, and good MC entry, and lysosomal escape abilities. The nanoparticles were found to exhibit enhanced retention in glomerular MCs due to anti-α8 integrin antibody mediation. In vivo and in vitro pharmacodynamic studies showed the enhanced efficacy of DXMS/siRNA@Au-ILs modified with α8 integrin antibodies in the treatment of glomerulonephritis. In addition, DXMS/siRNA@Au-ILs were capable of effectively reducing the expression levels of TNF-α, TGF-β1, and other cytokines, thereby improving pathological inflammatory and fibrotic conditions in the kidney, and significantly mediating the dual regulation of inflammation and fibrosis. In summary, our results demonstrated that effectively targeting the MCs of the glomerulus for drug delivery can inhibit local inflammation and fibrosis and produce better therapeutic effects, providing a new strategy and promising therapeutic approach for the development of targeted therapies for glomerular diseases.