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. 2022 Feb 19;41:68. doi: 10.1186/s13046-022-02272-x

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© The Author(s) 2022

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 11 — Dual blockade of CCL2 and CCL5 via LNP-mediated mRNA delivery of BisCCL2/5i polarizes macrophage M1 phenotype and reduces the immunosuppression in the TME. A Schematic of the mRNA-loaded LNPs. B In vivo transfection of Luc mRNA-LNPs after repeated administration (i.v., every 4 days, in total 3 doses). The luciferase was injected into mice 6 h post administration of Luc mRNA-LNPs, followed by measuring luc bioluminescence signal using IVIS imaging, n = 3. C The quantification of mCherry-positive cells expressed in murine orthotopic HCC tumor tissue 6 h after injection of mCherry mRNA-LNPs (mCherry mRNA: 0.5 mg kg − 1). mRNA is mainly expressed in monocytes (CD45 + CD11b+) and tumor cells (Hepa1–6-GFP+) (n = 8). D BisCCL2/5i expression in different organs 6 h after each administration of BisCCL2/5i mRNA-LNPs (mRNA: 1 mg kg − 1, i.v., 3 days apart), n = 6. The BisCCL2/5i mRNA was mainly expressed in liver tissue and repeated administration resulted in comparable protein level. E, F mRNA expression of classic M1 (E) and M2 (F) markers in HCC tumor tissues 48 h after systemic administration of formulated LNPs as a dose corresponding to 1 mg kg − 1 mRNA (Mock, HcRed mRNA). Each data point is an individual sample (n = 9); one-way ANOVA and Tukey’s multiple comparisons test. Change of the immunocellular composition in HCC TME 48 h following Mock mRNA-LNPs and BisCCL2/5i mRNA-LNPs treatments (mRNA: 1 mg kg − 1), measured by flow cytometry (n = 4; unpaired two-tailed Student’s t-test). G, H The percentage and cell counts of macrophages (G) and their M2 subtype (H) in total immune cells. I, J Representative flow dots of M1- and M2-phenotype macrophages (I) and ratio of M1/M2 (J). MΦ, macrophages (CD45 + CD11b + CD11c − Ly6C − Ly6G − F4/80+); M2, M2-phenotype macrophages (CD206+). Data are represented as the mean ± s.d. [164]