Abstract
Several immune cell-expressed miRNAs (miRs) are associated with altered prognostic outcome in cancer patients, suggesting that they may be potential targets for development of cancer therapies. Here, translucent zebrafish (Danio rerio) is utilized to demonstrate that genetic knockout or knockdown of one such miR, microRNA-223 (miR223), globally or specifically in leukocytes, does indeed lead to reduced cancer progression. As a first step toward potential translation to a clinical therapy, a novel strategy is described for reprogramming neutrophils and macrophages utilizing miniature artificial protocells (PCs) to deliver anti-miRs against the anti-inflammatory miR223. Using genetic and live imaging approaches, it is shown that phagocytic uptake of anti-miR223-loaded PCs by leukocytes in zebrafish (and by human macrophages in vitro) effectively prolongs their pro-inflammatory state by blocking the suppression of pro-inflammatory cytokines, which, in turn, drives altered immune cell-cancer cell interactions and ultimately leads to a reduced cancer burden by driving reduced proliferation and increased cell death of tumor cells. This PC cargo delivery strategy for reprogramming leukocytes toward beneficial phenotypes has implications also for treating other systemic or local immune-mediated pathologies.
Original language | English |
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Article number | 2202717 |
Number of pages | 20 |
Journal | Advanced Science |
Volume | 9 |
Issue number | 35 |
Early online date | 31 Oct 2022 |
DOIs | |
Publication status | Published - 19 Dec 2022 |
Bibliographical note
Funding Information:The authors thank Debi Ford for technical support with cryosectioning, Andrew Herman for assistance with FACS and Luminex, Katrina Entwistle for assistance with ELISpot, Qing Deng (Indiana, USA) for sharing the zebrafish line miR223KO, and Nikolay Ogryzko and Stephen Renshaw (Sheffield, UK) for sharing the zebrafish lines Tg() and Tg(). The authors also thank Victor Mulero (Murcia, Spain) for sharing the mouse monospecific anti‐zfIL1 antibody, Xinlong Fan for helping with protocell synthesis, members of P.M.’s, S.M.’s, Rebecca Richardson's, and Chrissy Hammond's labs for helpful discussions, and Yi Feng and Lucy MacCarthy‐Morrogh for reading drafts of the manuscript. The authors also thank members of the Wolfson Bioimaging Facility (University of Bristol, UK) for their help with imaging and image analysis, and the Zebrafish Facility of the University of Bristol for their services and contribution. Some schematic representations were, in part, generated with the support of Biorender. Funding: P.L.‐C. was funded by the Spanish Rafael del Pino Foundation and by a generous Bristol Cancer Bequest, and supported by a COVID‐19 Ph.D. extension from the Bristol Doctoral College through the University of Bristol, and, most recently, through a BrisEngBio Postdoctoral Grant. C.X. was funded by a Marie Curie Postdoctoral Fellowship (8082 H2020 PROTOBAC ERC 837197) and partly supported by the BBSRC (BB/P017320/1). C.E.S. and A.M.T. were funded by grants from NIHR BTRU in Red Blood Cell Products (NIHR‐BTRU‐2015‐10032), and NHSBT R&D (WP15‐05). T.C.L.O. was funded by a Wellcome Trust Ph.D. Studentship (8043 WT 108907/Z/15/Z). S.J.C. was funded by the Elizabeth Blackwell Institute, through its Wellcome Trust ISSF Award. S.M. was funded by the ERC Advanced Grant Scheme (EC‐2016‐ADG 740235). P.M. was funded by a CRUK Programme Grant (C20590/A15936), and a Wellcome Trust Investigator Award (WT:217169/Z/19/Z). The views expressed are those of the authors and not necessarily those of the NHS, NIHR, or the Department of Health and Social Care. il1β:GFP mpeg1:FRET β
Funding Information:
The authors thank Debi Ford for technical support with cryosectioning, Andrew Herman for assistance with FACS and Luminex, Katrina Entwistle for assistance with ELISpot, Qing Deng (Indiana, USA) for sharing the zebrafish line miR223KO, and Nikolay Ogryzko and Stephen Renshaw (Sheffield, UK) for sharing the zebrafish lines Tg(il1β:GFP) and Tg(mpeg1:FRET). The authors also thank Victor Mulero (Murcia, Spain) for sharing the mouse monospecific anti-zfIL1β antibody, Xinlong Fan for helping with protocell synthesis, members of P.M.’s, S.M.’s, Rebecca Richardson's, and Chrissy Hammond's labs for helpful discussions, and Yi Feng and Lucy MacCarthy-Morrogh for reading drafts of the manuscript. The authors also thank members of the Wolfson Bioimaging Facility (University of Bristol, UK) for their help with imaging and image analysis, and the Zebrafish Facility of the University of Bristol for their services and contribution. Some schematic representations were, in part, generated with the support of Biorender. Funding: P.L.-C. was funded by the Spanish Rafael del Pino Foundation and by a generous Bristol Cancer Bequest, and supported by a COVID-19 Ph.D. extension from the Bristol Doctoral College through the University of Bristol, and, most recently, through a BrisEngBio Postdoctoral Grant. C.X. was funded by a Marie Curie Postdoctoral Fellowship (8082 H2020 PROTOBAC ERC 837197) and partly supported by the BBSRC (BB/P017320/1). C.E.S. and A.M.T. were funded by grants from NIHR BTRU in Red Blood Cell Products (NIHR-BTRU-2015-10032), and NHSBT R&D (WP15-05). T.C.L.O. was funded by a Wellcome Trust Ph.D. Studentship (8043 WT 108907/Z/15/Z). S.J.C. was funded by the Elizabeth Blackwell Institute, through its Wellcome Trust ISSF Award. S.M. was funded by the ERC Advanced Grant Scheme (EC-2016-ADG 740235). P.M. was funded by a CRUK Programme Grant (C20590/A15936), and a Wellcome Trust Investigator Award (WT:217169/Z/19/Z). The views expressed are those of the authors and not necessarily those of the NHS, NIHR, or the Department of Health and Social Care.
Publisher Copyright:
© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.
Research Groups and Themes
- Max Planck Bristol
- Bristol BioDesign Institute