Comprehensive Summary Inflammation is associated with different stages of liver disease, including acute injury, fibrosis, cirrhosis, and hepatoma. During the progression of liver inflammation, activation of hepatic stellate cells (HSCs) and extracellular matrix (ECM) deposition are critical pathologies, and thus the combined therapy using HSCs and ECM as targets represents a promising strategy in the treatment of liver injury. Here, a novel CXCR4-inhibiting nanomedicine that can simultaneously deliver AMD3100 (CXCR4 antagonist) and siPAI-1 (siRNA of plasminogen activator inhibitor-1) was designed and developed to reverse liver fibrosis by inhibiting HSCs activation and degrading ECM deposition. With this goal in mind, a Zn (II) coordinated polymeric AMD3100 named PAMD/Zn polymer with siRNA delivery and CXCR4 antagonism capabilities was synthesized. Overall, our results suggest that PAMD/Zn recruits pro-inflammatory cells for fibrogenesis and inhibits the activation of HSCs for fibrolysis at various stages of liver injury. Its use in conjunction with PAI-1 silencing achieved satisfactory therapeutic efficacy in liver injury and fibrosis. The derivative CXCR4-inhibiting nanomedicine is a versatile platform that offers valuable benefits for the treatment of liver diseases. This article is protected by copyright. All rights reserved.
Jingwen Dong,Chenfei Zhu,Ying Huang,Quanhao Li,Jing Li,Zheng Wang,Yixin Wang,Zhanwei Zhou,Minjie Sun
Fibrosis is one of the key factors that lead to the immune exclusion of solid tumors. Although degradation of fiber is a promising strategy, its application was still bottlenecked by the side effects of causing metastasis, resulting in the failure of immunotherapy. Here, we developed an antimetastatic polymer (HPA) for the delivery of chemo-drug and antifibrotic siPAI-1 to form the nano-permeator. Nano-permeator shrank after protonation and deeply penetrated into the tumor core to down-regulate the expression of PAI-1 for antifibrosis, and further promoted the sustained infiltration and activation of T cells for killing tumor cells. Moreover, metastasis after fiber elimination was prevented by multivalent CXCR4 antagonistic HPA to reduce the attraction of CXCL12 secreted by distant organs. The administration of stroma-alleviated immunotherapy increased the infiltration of CD8 + T cells to 52.5% in tumor tissues, inhibiting nearly 90% metastasis by HPA in distant organs. The nano-permeator reveals the mechanism and correlation between antifibrosis and antimetastasis and was believed to be the optimizing immunotherapy for solid fibrotic tumors.
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