HUI-TENG CHENGHuang, Hsi-ChienHsi-ChienHuangLee, Tsung-YingTsung-YingLeeLiao, Yu-HuiYu-HuiLiaoSheng, Yi-HuaYi-HuaShengJin, Pei-RuPei-RuJinHuang, Kuan-WeiKuan-WeiHuangChen, Ling-HsuanLing-HsuanChenYI-TING CHENLiu, Zi-YanZi-YanLiuLin, Tzu-ChiehTzu-ChiehLinWang, Hsueh-ChengHsueh-ChengWangCHENG-HAN CHAOJuang, I PuI PuJuangCHI-TING SUKUO-HOW HUANGSHUEI-LIONG LINJANE WANGSung, Yun-ChiehYun-ChiehSungChen, YunchingYunchingChen2022-06-202022-06-202022-0601683659https://scholars.lib.ntu.edu.tw/handle/123456789/613125Fibrosis is an excessive accumulation of the extracellular matrix within solid organs in response to injury and a common pathway that leads functional failure. No clinically approved agent is available to reverse or even prevent this process. Herein, we report a nanotechnology-based approach that utilizes a drug carrier to deliver a therapeutic cargo specifically to fibrotic kidneys, thereby improving the antifibrotic effect of the drug and reducing systemic toxicity. We first adopted in vitro-in vivo combinatorial phage display technology to identify peptide ligands that target myofibroblasts in mouse unilateral ureteral obstruction (UUO)-induced fibrotic kidneys. We then engineered lipid-coated poly(lactic-co-glycolic acid) nanoparticles (NPs) with fibrotic kidney-homing peptides on the surface and sorafenib, a potent antineoplastic multikinase inhibitor, encapsulated in the core. Sorafenib loaded in the myofibroblast-targeted NPs significantly reduced the infiltration of α-smooth muscle actin-expressing myofibroblasts and deposition of collagen I in UUO-treated kidneys and enhanced renal plasma flow measured by Technetium-99m mercaptoacetyltriglycine scintigraphy. This study demonstrates the therapeutic potential of the newly identified peptide fragments as anchors to target myofibroblasts and represents a strategic advance for selective delivery of sorafenib to treat renal fibrosis. SIGNIFICANCE STATEMENT: Renal fibrosis is a pathological feature accounting for the majority of issues in chronic kidney disease (CKD), which may progress to end-stage renal disease (ESRD). This manuscript describes a myofibroblast-targeting drug delivery system modified with phage-displayed fibrotic kidney-homing peptides. By loading the myofibroblast-targeting nanoparticles (NPs) with sorafenib, a multikinase inhibitor, the NPs could suppress collagen synthesis in cultured human myofibroblasts. When given intravenously to mice with UUO-induced renal fibrosis, sorafenib loaded in myofibroblast-targeting NPs significantly ameliorated renal fibrosis. This approach provides an efficient therapeutic option to renal fibrosis. The myofibroblast-targeting peptide ligands and nanoscale drug carriers may be translated into clinical application in the future.enPhage display; Renal fibrosis; Sorafenib[SDGs]SDG3journal article10.1016/j.jconrel.2022.04.004354295752-s2.0-85129341981https://scholars.lib.ntu.edu.tw/handle/123456789/610966