Abstract
BackgroundDespite 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.ResultsThe 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.ConclusionThe tubule-specific K3-HBc/CLT represented a promising option to realize precise treatment for renal fibrosis.
Highlights
Chronic kidney disease (CKD) is a major public health concern worldwide [1]
CLT attenuates unilateral ureteral obstruction (UUO)‐induced renal fibrosis with severe toxicity We first studied the therapeutic effect of CLT
We found that CLT could decrease this value to 17.06 ± 3.22, implying that more than 90% collagen was eliminated. α-smooth muscle actin (α-SMA), a major morphological characteristic of myofibroblasts, plays a crucial role in the development and progression of renal tubulointerstitial fibrosis [18]
Summary
Many therapeutic approaches have focused on fibroblasts and myofibroblasts as these cells are the effectors of renal fibrosis [5]. Tubular epithelial cells are essential for injury They can adopt different repair mechanisms to survive injury and recover normal kidney function. As the injury is severe and persistent, normal regeneration mechanisms may not work, and tubular epithelial. 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. The efficacy of K3-HBc/CLT NCs were demonstrated in Unilateral ureteral obstruction (UUO)-induced renal fibrosis
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