Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou 450003, China.
Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
Nano Lett. 2024 Sep 4;24(35):11097-11107. doi: 10.1021/acs.nanolett.4c03315. Epub 2024 Aug 26.
Renal fibrosis lacks effective nephroprotective drugs in clinical settings due to poor accumulation of therapeutic agents in damaged kidneys, underscoring the urgent need for advanced renal-targeted delivery systems. Herein, we exploited the significantly increased expression of the leucine-rich α-2 glycoprotein 1 (LRG1) protein during renal fibrosis to develop a novel drug delivery system. Our engineered nanocarrier, DEN, preferentially targets fibrotic kidneys via the decorated ET peptide's high affinity for LRG1. Once internalized by damaged renal cells, DEN releases its encapsulated nintedanib, triggered by the active caspase-3 protease, disrupting the nanomedicine's structural integrity. The released nintedanib effectively reduces the level of expression of the extracellular matrix and impedes the progression of renal fibrosis by inhibiting the transforming growth factor-β (TGF-β)-Smad2/3 pathway. Our comprehensive and studies validate DEN's antifibrotic efficacy, emphasizing LRG1's potential in renal targeted drug delivery and introducing an innovative approach to nanomedicine for treating renal fibrosis.
由于治疗药物在受损肾脏中的积累不良，肾脏纤维化在临床环境中缺乏有效的肾脏保护药物，这突显了对先进的肾脏靶向递药系统的迫切需求。在此，我们利用肾脏纤维化过程中富含亮氨酸的α-2 糖蛋白 1（LRG1）蛋白的显著上调，开发了一种新型药物递药系统。我们设计的纳米载体 DEN 通过精心设计的 ET 肽对 LRG1 的高亲和力，优先靶向纤维化肾脏。一旦被受损的肾细胞内化，DEN 就会被激活的 caspase-3 蛋白酶触发释放其包封的尼达尼布，破坏纳米药物的结构完整性。释放的尼达尼布通过抑制转化生长因子-β（TGF-β）-Smad2/3 通路有效降低细胞外基质的表达水平，并阻止肾脏纤维化的进展。我们的综合研究验证了 DEN 的抗纤维化功效，强调了 LRG1 在肾脏靶向药物递药中的潜力，并为治疗肾脏纤维化的纳米医学引入了一种创新方法。
