Liver fibrosis could be the last hope for treating liver cancer and remodeling of the hepatic microenvironment has emerged as a strategy to promote the ablation of liver fibrosis. In recent years, especially with the rapid development of nanomedicine, hepatic microenvironment therapy has been widely researched in studies concerning liver cancer and fibrosis. In this comprehensive review, we summarized recent advances in nano therapy-based remodeling of the hepatic microenvironment. Firstly, we discussed novel strategies for regulatory immune suppression caused by capillarization of liver sinusoidal endothelial cells (LSECs) and macrophage polarization. Furthermore, metabolic reprogramming and extracellular matrix (ECM) deposition are caused by the activation of hepatic stellate cells (HSCs). In addition, recent advances in ROS, hypoxia, and impaired vascular remodeling in the hepatic fibrotic microenvironment due to ECM deposition have also been summarized. Finally, emerging nanotherapeutic approaches based on correlated signals were discussed in this review. We have proposed novel strategies such as engineered nanotherapeutics targeting antigen-presenting cells (APCs) or direct targeting T cells in liver fibrotic immunotherapy to be used in preventing liver fibrosis. In summary, this comprehensive review illustrated the opportunities in drug targeting and nanomedicine, and the current challenges to be addressed. Graphical Abstract

Liver fibrosis is a process of over-extracellular matrix (ECM) aggregation and angiogenesis, which develops into cirrhosis and hepatocellular carcinoma (HCC). With the increasing pressure of liver fibrosis, new therapeutics to cure this disease requires much attention. Exosome-cargoed microRNAs (miRNAs) are emerging approaches in the precision of the liver fibrotic paradigm. In this review, we outlined the different types of hepatic cells derived miRNAs that drive intra-/extra-cellular interactive communication in liver fibrosis with different physiological and pathological processes. Specifically, we highlighted the possible mechanism of liver fibrosis pathogenesis associated with immune response and angiogenesis. In addition, potential clinical biomarkers and different stem cell transplant-derived miRNAs-based therapeutic strategies in liver fibrosis were summarized in this review. miRNAs-based approaches might help researchers devise new candidates for the cell-free treatment of liver fibrosis.

Background: The main tumors in chicken caused by avian leukemia virus (ALV) are leukemia. The bone marrow microenvironment is the genesis of leukemia, but little is known about the state of the chicken bone marrow microenvironment under avian leukemia virus subgroup J (ALV-J) infection. Meanwhile, alterations in the immune status of the bone marrow microenvironment are closely associated with the development of leukemia. Results: In this article, scRNA-seq was used on chicken bone marrow lymphocytes with different states of ALV-J infection to identify marker genes, cell states, and subgroups of lymphocytes. A total of eighteen clusters and their potential marker genes were identified. Among them, eight T cell clusters, two B cell clusters, and five tumor-like cell clusters were identified, whereas three clusters could not be identified. Among ten lymphocyte clusters, double-positive T cells (cluster_2), B1-like B cells (cluster_7), and cytotoxic T cells (cluster_9) responded strongly to ALV-J infection. Their differentially expressed genes were highly enriched in immune-related pathways and viral infection-related pathways, and they accounted for a large proportion and variation in samples with different clinical symptoms of ALV-J infection. The immunosuppressive state of bone marrow microenvironment was stronger after the occurrence of more severe ALV-J infection. Regulatory T cells and CTLA4T cells were more predominant in samples with more severe ALV-J infection. Immunosuppressive factors TGFB1 and IL16 were expressed in multiple clusters, and the expression of TGFB1 and IL16 was higher in samples with more severe ALV-J infection. ALV-J infected all clusters, but in the same cluster of cells, a fraction of cells expressed ALV-J transcripts, whereas the other fraction did not. Meanwhile, in the same cluster of cells expressing ALV-J transcripts, the pathway associated with intracellular antiviral infection, “Signaling by Rho Family GTPases” was activated. By using IPA analysis software, some upstream regulatory elements (MYCand MCYN) responsible for this difference were predicted. Conclusions: Decreased immunocompetence in the bone marrow microenvironment caused by ALV-J maybe associated with occurrence of leukemia. The cells in the same cluster showed different susceptibility to ALV-J. Our results could contribute to the understanding of bone marrow lymphocytes in different infection states of ALV-J.