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Multifunctional oncolytic nanoparticles deliver self-replicating IL-12 RNA to eliminate established tumors and prime systemic immunity
Open accessAbstract
Therapies that synergistically stimulate immunogenic cancer cell death (ICD), inflammation, and immune priming are of great interest for cancer immunotherapy. However, even multi-agent therapies often fail to trigger all of the steps necessary for self-sustaining anti-tumor immunity. Here we describe self-replicating RNAs encapsulated in lipid nanoparticles (LNP-replicons), which combine three key elements: (1) an LNP composition that potently promotes ICD, (2) RNA that stimulates danger sensors in transfected cells, and (3) RNA-encoded IL-12 for modulation of immune cells. Intratumoral administration of LNP-replicons led to high-level expression of IL-12, stimulation of a type I interferon response, and cancer cell ICD, resulting in a highly inflamed tumor microenvironment and priming of systemic anti-tumor immunity. In several mouse models of cancer, a single intratumoral injection of replicon-LNPs eradicated large established tumors, induced protective immune memory, and enabled regression of distal uninjected tumors. LNP-replicons are thus a promising multifunctional single-agent immunotherapeutic.
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A pro-inflammatory tumour microenvironment can be induced by lipid nanoparticle-mRNA formulations delivering cytokines or co-stimulatory molecules.
“Alternatively to vaccination, a pro-inflammatory tumour microenvironment can be induced by lipid nanoparticle–mRNA formulations delivering cytokines or co-stimulatory molecules33,106,161,163,214 (Table 2).”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [106]
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Metadata
- Authors
- Li, Y., Su, Z., Zhao, W., Zhang, X., Momin, N., Zhang, C., Wittrup, K. D., Dong, Y., Irvine, D. J., & Weiss, R.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- The Ohio State University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Dong, Yizhou
- Irvine, Darrell J.
- Weiss, Ron
- ORCID
- Venue
- Nature Cancer
- Published
- 2020-08-10
- Volume
- 1
- Issue
- 9
- Pages
- 882-893
- ISSN
- 2662-1347 (ISSN-L)
- PMC
- PMC8386348
- OpenAlex
- W3047822613
- Cited by
- 233
- References
- 47
- Citations by year
- 2026: 24 · 2025: 45 · 2024: 58 · 2023: 43 · 2022: 34 · 2021: 26 · 2020: 3
- FWCI
- 9.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Cancer (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute (P30-CA14051, CA20618)
- Howard Hughes Medical Institute
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (CA20618)
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R35GM119679)
- Professor Sylvan G. Frank Graduate Fellowship
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- self-replicating RNA, IL-12, immunogenic cancer cell death, cancer immunotherapy, type I interferon response, tumor microenvironment inflammation, systemic antitumor immunity, immunological memory, intratumoral injection
- MeSH terms
- Animals, Immunotherapy, Liposomes, Neoplasms, RNA, Interleukin-12, Mice, Nanoparticles, Tumor Microenvironment
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