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journal article·2024-05-07Open access

Nanoparticle Retinoic Acid-Inducible Gene I Agonist for Cancer Immunotherapy

Lihong Wang-Bishop, Mohamed Wehbe, Lucinda E. Pastora, Jinming Yang, Blaise R. Kimmel, Kyle M. Garland, Kyle W. Becker, Carcia S. Carson, Eric W. Roth, Katherine N. Gibson-Corley, David Ulkoski, Venkata Krishnamurthy, Olga Fedorova, Ann Richmond, Anna Marie Pyle, John T. Wilson

ACS Nano· Volume 18· Issue 18
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Source abstract

Abstract

High Resolution Image Download MS PowerPoint Slide Pharmacological activation of the retinoic acid-inducible gene I (RIG-I) pathway holds promise for increasing tumor immunogenicity and improving the response to immune checkpoint inhibitors (ICIs). However, the potency and clinical efficacy of 5′-triphosphate RNA (3pRNA) agonists of RIG-I are hindered by multiple pharmacological barriers, including poor pharmacokinetics, nuclease degradation, and inefficient delivery to the cytosol where RIG-I is localized. Here, we address these challenges through the design and evaluation of ionizable lipid nanoparticles (LNPs) for the delivery of 3p-modified stem-loop RNAs (SLRs). Packaging of SLRs into LNPs (SLR-LNPs) yielded surface charge-neutral nanoparticles with a size of ∼100 nm that activated RIG-I signaling in vitro and in vivo. SLR-LNPs were safely administered to mice via both intratumoral and intravenous routes, resulting in RIG-I activation in the tumor microenvironment (TME) and the inhibition of tumor growth in mouse models of poorly immunogenic melanoma and breast cancer. Significantly, we found that systemic administration of SLR-LNPs reprogrammed the breast TME to enhance the infiltration of CD8 + and CD4 + T cells with antitumor function, resulting in enhanced response to αPD-1 ICI in an orthotopic EO771 model of triple-negative breast cancer. Therapeutic efficacy was further demonstrated in a metastatic B16.F10 melanoma model, with systemically administered SLR-LNPs significantly reducing lung metastatic burden compared to combined αPD-1 + αCTLA-4 ICI. Collectively, these studies have established SLR-LNPs as a translationally promising immunotherapeutic nanomedicine for potent and selective activation of RIG-I with the potential to enhance response to ICIs and other immunotherapeutic modalities.
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Research context

Nanomaterials

OpenAlex topics: Immunotherapy and Immune Responses · interferon and immune responses · Immune Cell Function and Interaction

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee 37212, United States

Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States

Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee 37212, United States

Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37212, United States

Northwestern University Atomic and Nanoscale Characterization Experimental (NUANCE) Center, Northwestern University, Evanston, Illinois 60208, United States

Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States

Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States

Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, Boston, Massachusetts 02451, United States

Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06520, United States

Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, United States

Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States

Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37212, United States

Vanderbilt Institute of Nanoscale Science and Engineering, Vanderbilt University, Nashville, Tennessee 37212, United States

Funding

Vanderbilt University · Canadian Institutes of Health Research · Division of Graduate Education · Congressionally Directed Medical Research Programs · Pharmaceutical Research and Manufacturers of America Foundation · Vanderbilt Ingram Cancer Center

References (56)

Show source-provided references
1. 10.1126/science.aar406010.1126/science.aar4060 ↗
2. 10.1158/2159-8290.CD-20-168010.1158/2159-8290.CD-20-1680 ↗
3. 10.1016/j.ccell.2018.03.00510.1016/j.ccell.2018.03.005 ↗
4. 10.1038/s41573-018-0007-y10.1038/s41573-018-0007-y ↗
5. 10.1158/2326-6066.CIR-18-027710.1158/2326-6066.CIR-18-0277 ↗
6. 10.1038/s41586-019-1593-510.1038/s41586-019-1593-5 ↗
7. 10.1038/nrd.2017.26410.1038/nrd.2017.264 ↗
8. 10.1016/j.virol.2015.02.01710.1016/j.virol.2015.02.017 ↗
9. 10.1126/science.113250510.1126/science.1132505 ↗
10. 10.1111/imr.1302210.1111/imr.13022 ↗
11. 10.1126/sciadv.170185410.1126/sciadv.1701854 ↗
12. 10.1371/journal.ppat.100329810.1371/journal.ppat.1003298 ↗
13. 10.1038/nm.188710.1038/nm.1887 ↗
14. 10.1172/JCI12147610.1172/JCI121476 ↗
15. 10.1038/s41586-018-0768-910.1038/s41586-018-0768-9 ↗
16. 10.1126/sciimmunol.aau894310.1126/sciimmunol.aau8943 ↗
17. 10.1021/acscentsci.0c0056810.1021/acscentsci.0c00568 ↗
18. 10.1038/s41573-019-0043-210.1038/s41573-019-0043-2 ↗
19. 10.1038/s41578-021-00358-010.1038/s41578-021-00358-0 ↗
20. 10.1021/acs.accounts.9b0036810.1021/acs.accounts.9b00368 ↗
21. 10.1038/s41573-021-00283-510.1038/s41573-021-00283-5 ↗
22. 10.1038/s41565-019-0591-y10.1038/s41565-019-0591-y ↗
23. 10.1158/0008-5472.CAN-11-385010.1158/0008-5472.CAN-11-3850 ↗
24. 10.1084/jem.2019080110.1084/jem.20190801 ↗
25. 10.1007/s00262-022-03191-810.1007/s00262-022-03191-8 ↗
26. 10.1038/s41467-021-27493-010.1038/s41467-021-27493-0 ↗
27. 10.1158/1535-7163.MCT-16-030910.1158/1535-7163.MCT-16-0309 ↗
28. 10.1158/0008-5472.CAN-18-073010.1158/0008-5472.CAN-18-0730 ↗
29. 10.1172/JCI3715510.1172/JCI37155 ↗
30. 10.1016/j.ejca.2021.08.00410.1016/j.ejca.2021.08.004 ↗
31. 10.1093/annonc/mdy42310.1093/annonc/mdy423 ↗
32. 10.1038/s41586-020-2537-910.1038/s41586-020-2537-9 ↗
33. 10.1158/2326-6066.CIR-21-072210.1158/2326-6066.CIR-21-0722 ↗
34. 10.1016/S0140-6736(20)32531-910.1016/S0140-6736(20)32531-9 ↗
35. 10.1158/0008-5472.CAN-17-134010.1158/0008-5472.CAN-17-1340 ↗
36. 10.1038/nrclinonc.2016.6510.1038/nrclinonc.2016.65 ↗
37. 10.1038/s41467-021-23244-310.1038/s41467-021-23244-3 ↗
38. 10.1016/j.jconrel.2020.10.06010.1016/j.jconrel.2020.10.060 ↗
39. 10.1016/j.ymthe.2018.11.01210.1016/j.ymthe.2018.11.012 ↗
40. 10.1039/C8BM01064A10.1039/C8BM01064A ↗
41. 10.1002/jev2.1218710.1002/jev2.12187 ↗
42. 10.1097/CJI.0b013e3181f5dfa710.1097/CJI.0b013e3181f5dfa7 ↗
43. 10.2174/156652322166621070513023810.2174/1566523221666210705130238 ↗
44. 10.1016/j.ejpb.2018.05.03410.1016/j.ejpb.2018.05.034 ↗
45. 10.1039/c000190b10.1039/c000190b ↗
46. 10.1038/s41565-020-0669-610.1038/s41565-020-0669-6 ↗
47. 10.1016/j.jconrel.2020.11.01710.1016/j.jconrel.2020.11.017 ↗
48. 10.1038/nature1830010.1038/nature18300 ↗
49. 10.1038/s41565-022-01225-x10.1038/s41565-022-01225-x ↗
50. 10.1038/s41563-022-01251-z10.1038/s41563-022-01251-z ↗
51. 10.1038/s41563-019-0566-210.1038/s41563-019-0566-2 ↗
52. 10.1038/s41565-018-0342-510.1038/s41565-018-0342-5 ↗
53. 10.1021/acs.bioconjchem.7b0069710.1021/acs.bioconjchem.7b00697 ↗
54. 10.1016/j.cell.2021.08.00410.1016/j.cell.2021.08.004 ↗
55. 10.1002/anie.20120326310.1002/anie.201203263 ↗
56. 10.1021/acsnano.0c0276510.1021/acsnano.0c02765 ↗