Abstract：
Liver fibrosis is a chronic pathological condition lacking specific clinical treatments. Stem cells, with notable potential in regenerative medicine, offer promise in treating liver fibrosis. However, stem cell therapy is hindered by potential immunological rejection, carcinogenesis risk, efficacy variation, and high cost. Stem cell secretome-based cell-free therapy offers potential solutions to address these challenges, but it is limited by low delivery efficiency and rapid clearance. Herein, an innovative approach for in situ implantation of smart microneedle (MN) arrays enabling precisely controlled delivery of multiple therapeutic agents directly into fibrotic liver tissues is developed. By integrating cell-free and platinum-based nanocatalytic combination therapy, the MN arrays can deactivate hepatic stellate cells. Moreover, they promote excessive extracellular matrix degradation by more than 75%, approaching normal levels. Additionally, the smart MN arrays can provide hepatocyte protection while reducing inflammation levels by ≈70-90%. They can also exhibit remarkable capability in scavenging almost 100% of reactive oxygen species and alleviating hypoxia. Ultimately, this treatment strategy can effectively restrain fibrosis progression. The comprehensive in vitro and in vivo experiments, supplemented by proteome and transcriptome analyses, substantiate the effectiveness of the approach in treating liver fibrosis, holding immense promise for clinical applications.
摘要：
肝纤维化是一种缺乏特异性临床治疗的慢性病理状况。干细胞,在再生医学方面具有显著的潜力，提供在治疗肝纤维化的承诺。然而,干细胞治疗受到潜在免疫排斥反应的阻碍，致癌风险，功效变异，和高成本。基于干细胞分泌组的无细胞治疗为应对这些挑战提供了潜在的解决方案。但它是有限的低交货效率和快速清除。在这里，开发了一种用于原位植入智能微针（MN）阵列的创新方法，该方法能够精确控制地将多种治疗剂直接递送到纤维化肝组织中。通过整合无细胞和铂基纳米催化联合治疗，MN阵列可以使肝星状细胞失活。此外，它们促进超过75%的细胞外基质过度降解，接近正常水平。此外,智能MN阵列可以提供肝细胞保护，同时将炎症水平降低约70-90%。它们还可以在清除几乎100％的活性氧和缓解缺氧方面表现出非凡的能力。最终,这种治疗策略可以有效抑制纤维化进展。全面的体外和体内实验，补充蛋白质组和转录组分析，证实该方法治疗肝纤维化的有效性，拥有巨大的临床应用前景。
