2. Academic Validation
  3. Tubule-specific protein nanocages potentiate targeted renal fibrosis therapy

Tubule-specific protein nanocages potentiate targeted renal fibrosis therapy

  • J Nanobiotechnology. 2021 May 26;19(1):156. doi: 10.1186/s12951-021-00900-w.
Xuan Zhang  # 1,  Qian Chen  # 2,  Liyuan Zhang 1,  Haiping Zheng 3,  Chunjie Lin 4,  Qunfang Yang 1,  Tao Liu 1,  Haigang Zhang 1,  Xiaohong Chen 1,  Lei Ren 5,  Wenjun Shan 6 7
Affiliations

Affiliations

  • 1 Department of Pharmacology, College of Pharmacy and Laboratory Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, People's Republic of China.
  • 2 Biomedical Analysis Center, College of Basic Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, People's Republic of China.
  • 3 School of Medicine, Xiamen University, Xiamen, 361102, People's Republic of China.
  • 4 School of Life Sciences, Xiamen University, Xiamen, 361102, People's Republic of China.
  • 5 Department of Biomaterials, College of Materials, Xiamen University, Xiamen, 361005, People's Republic of China. renlei@xmu.edu.cn.
  • 6 Department of Pharmacology, College of Pharmacy and Laboratory Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, People's Republic of China. wjshan@tmmu.edu.cn.
  • 7 School of Medicine, Huaqiao University, Quanzhou, 362021, People's Republic of China. wjshan@tmmu.edu.cn.
  • # Contributed equally.
PMID: 34039349 DOI: 10.1186/s12951-021-00900-w
Abstract

Background: Despite the dramatic advances in modern medicine, efficient therapeutic measures for renal fibrosis remain limited. Celastrol (CLT) is effective in treating renal fibrosis in rat models, while causing severe systemic toxicity. Thus, we designed a tubule-specific nanocage (K3-HBc NCs) that effectively deliver CLT to tubular epithelial cell in a virus-like manner. The targeting ligand (K3) to tubular epithelial cells was displayed on the surface of Hepatitis B core protein (HBc) NCs by genetic fusion to the major immunodominant loop region. Ultra-small CLT nanodots were subtly encapsulated into the cavity through electrostatic interaction with the disassembly and reassembly of K3-HBc NCs, to yield K3-HBc/CLT complex. The efficacy of K3-HBc/CLT NCs were demonstrated in Unilateral ureteral obstruction (UUO)-induced renal fibrosis.

Results: The self-assembled K3-HBc/CLT could specifically target tubular epithelial cells via affinity with K3 ligand binding to the megalin receptor, significantly attenuating renal fibrosis. Remarkably, K3-HBc/CLT NCs significantly increased therapeutic efficacy and reduced the systemic toxicity in comparison with free CLT in UUO-induced mouse renal fibrosis model. Importantly, analysis of RNA Sequencing data suggested that the anti-fibrotic effect of K3-HBc/CLT could be attributed to suppression of premature senescence in tubular epithelial cells via p21Cip1 and p16Ink4a pathway.

Conclusion: The tubule-specific K3-HBc/CLT represented a promising option to realize precise treatment for renal fibrosis.

Keywords

Celastrol; Cell senescence; Protein nanocage; Renal fibrosis; Target therapy.

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