肝纤维化是几乎所有慢性肝病中出现的渐进性组织学表现。持续存在的肝纤维化最终可能发展为肝硬化或肝细胞癌。然而，逆转肝纤维化的策略仍然有限。因此，研发了生物仿生纳米调节器（P-ZIF8-cirDNAzyme），用于影响肝脏中的胶原合成和降解，重构胶原微环境。发现Zn（II）干预可以通过失活脯氨酸4-羟化酶并影响多个疤痕形成相关信号通路，有效抑制激活的肝星状细胞（aHSC）中的胶原合成。同时，利用Zn（II）依赖的环形DNA酶（cirDNAzyme）可有效沉默金属蛋白酶组织抑制物质-1，加速胶原降解。它们共同作用以恢复胶原沉积和降解之间的平衡。此外，ZIF-8-cirDNAzyme被血小板膜（PM）包覆，通过PM的炎症趋性和CD62p-CD44相互作用精确地靶向aHSC。在四氯化碳诱导的纤维化小鼠中，P-ZIF-8-cirDNAzyme表现出强大的抗纤维化效果，将胶原表达大幅减少了73.12％，并将肝功能恢复到几乎正常水平。本研究提出了一个前瞻性平台，可以使离子干扰和基因沉默共同在aHSC中发挥作用，逆转肝纤维化。© 2023 Wiley-VCH GmbH发表的先进科学由作者提供。

Liver fibrosis is a progressive histological manifestation that happens in almost all chronic liver diseases. An unabated liver fibrosis may eventually develop into liver cirrhosis or hepatocellular carcinoma. Yet, the strategy for reversal of liver fibrosis is still limited. Herein, a biomimetic nano-regulator (P-ZIF8-cirDNAzyme) is developed to affect both collagen synthesis and degradation in liver to remodel collagen microenvironment. It is found that Zn (II) interference can efficiently inhibit collagen synthesis in activated hepatic stellate cells (aHSC) by inactivating proline 4 hydroxylase and affecting many fibrosis-related signaling pathways. Meanwhile, Zn (II)-dependent circular DNAzymes (cirDNAzymes) are used to efficiently silence tissue inhibitors of metalloproteinase-1, accelerating the degradation of collagen. They act in concert to recover the balance between collagen deposition and degradation. Additionally, ZIF-8-cirDNAzyme is coated by platelet membrane (PM) for precisely targeting aHSC via PM's inflammatory tropism and CD62p-CD44 interaction. In carbon tetrachloride-induced fibrotic mice, P-ZIF-8-cirDNAzyme shows a potent anti-fibrotic effect, greatly reducing the expression of collagen by 73.12% and restoring liver function nearly to normal. This work proposes a prospective platform enabling ion interference and gene silencing, collectively acting in aHSC for reversal of liver fibrosis.© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.