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Biodegradable lipophilic polymeric mRNA nanoparticles for ligand-free targeting of splenic dendritic cells for cancer vaccination
Nanoparticle (NP)-based mRNA cancer vaccines hold great promise to realize personalized cancer treatments. To advance this technology requires delivery formulations for efficient intracellular delivery to antigen-presenting cells. We developed a class of bioreducible lipophilic poly(beta-amino ester...
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| Published in: | Proceedings of the National Academy of Sciences - PNAS 2023-06, Vol.120 (26), p.e2301606120 |
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| container_issue | 26 |
| container_start_page | e2301606120 |
| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Ben-Akiva, Elana Karlsson, Johan Hemmati, Shayan Yu, Hongzhe Tzeng, Stephany Y Pardoll, Drew M Green, Jordan J |
| description | Nanoparticle (NP)-based mRNA cancer vaccines hold great promise to realize personalized cancer treatments. To advance this technology requires delivery formulations for efficient intracellular delivery to antigen-presenting cells. We developed a class of bioreducible lipophilic poly(beta-amino ester) nanocarriers with quadpolymer architecture. The platform is agnostic to the mRNA sequence, with one-step self-assembly allowing for delivery of multiple antigen-encoding mRNAs as well as codelivery of nucleic acid-based adjuvants. We examined structure-function relationships for NP-mediated mRNA delivery to dendritic cells (DCs) and identified that a lipid subunit of the polymer structure was critical. Following intravenous administration, the engineered NP design facilitated targeted delivery to the spleen and preferential transfection of DCs without the need for surface functionalization with targeting ligands. Treatment with engineered NPs codelivering antigen-encoding mRNA and toll-like receptor agonist adjuvants led to robust antigen-specific CD8+ T cell responses, resulting in efficient antitumor therapy in in vivo models of murine melanoma and colon adenocarcinoma. |
| doi_str_mv | 10.1073/pnas.2301606120 |
| format | article |
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To advance this technology requires delivery formulations for efficient intracellular delivery to antigen-presenting cells. We developed a class of bioreducible lipophilic poly(beta-amino ester) nanocarriers with quadpolymer architecture. The platform is agnostic to the mRNA sequence, with one-step self-assembly allowing for delivery of multiple antigen-encoding mRNAs as well as codelivery of nucleic acid-based adjuvants. We examined structure-function relationships for NP-mediated mRNA delivery to dendritic cells (DCs) and identified that a lipid subunit of the polymer structure was critical. Following intravenous administration, the engineered NP design facilitated targeted delivery to the spleen and preferential transfection of DCs without the need for surface functionalization with targeting ligands. Treatment with engineered NPs codelivering antigen-encoding mRNA and toll-like receptor agonist adjuvants led to robust antigen-specific CD8+ T cell responses, resulting in efficient antitumor therapy in in vivo models of murine melanoma and colon adenocarcinoma.</description><identifier>ISSN: 0027-8424</identifier><identifier>ISSN: 1091-6490</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2301606120</identifier><identifier>PMID: 37339211</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Adenocarcinoma ; Adenocarcinoma - pathology ; Adjuvants ; Adjuvants, Immunologic ; Animal models ; Animals ; Antigen-presenting cells ; Antigens ; Biodegradation ; Biological Sciences ; Cancer ; Cancer therapies ; Cancer Vaccines ; CD8 antigen ; Colonic Neoplasms - pathology ; Colonic Neoplasms - therapy ; delivery ; Dendritic Cells ; Humans ; Intravenous administration ; Ligands ; Lipids ; Lipophilic ; Lipophilicity ; Lymphocytes ; Lymphocytes T ; Melanoma ; Mice ; mRNA ; nanoparticle ; Nanoparticles ; Nanoparticles - chemistry ; Nucleic acids ; Physical Sciences ; Polymers ; Polymers - chemistry ; RNA, Messenger - genetics ; Self-assembly ; Spleen ; Structure-function relationships ; Toll-like receptors ; Transfection ; Vaccination ; vaccine ; Vaccines</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2023-06, Vol.120 (26), p.e2301606120</ispartof><rights>Copyright National Academy of Sciences Jun 27, 2023</rights><rights>Copyright © 2023 the Author(s). 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To advance this technology requires delivery formulations for efficient intracellular delivery to antigen-presenting cells. We developed a class of bioreducible lipophilic poly(beta-amino ester) nanocarriers with quadpolymer architecture. The platform is agnostic to the mRNA sequence, with one-step self-assembly allowing for delivery of multiple antigen-encoding mRNAs as well as codelivery of nucleic acid-based adjuvants. We examined structure-function relationships for NP-mediated mRNA delivery to dendritic cells (DCs) and identified that a lipid subunit of the polymer structure was critical. Following intravenous administration, the engineered NP design facilitated targeted delivery to the spleen and preferential transfection of DCs without the need for surface functionalization with targeting ligands. Treatment with engineered NPs codelivering antigen-encoding mRNA and toll-like receptor agonist adjuvants led to robust antigen-specific CD8+ T cell responses, resulting in efficient antitumor therapy in in vivo models of murine melanoma and colon adenocarcinoma.</description><subject>Adenocarcinoma</subject><subject>Adenocarcinoma - pathology</subject><subject>Adjuvants</subject><subject>Adjuvants, Immunologic</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antigen-presenting cells</subject><subject>Antigens</subject><subject>Biodegradation</subject><subject>Biological Sciences</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Cancer Vaccines</subject><subject>CD8 antigen</subject><subject>Colonic Neoplasms - pathology</subject><subject>Colonic Neoplasms - therapy</subject><subject>delivery</subject><subject>Dendritic Cells</subject><subject>Humans</subject><subject>Intravenous administration</subject><subject>Ligands</subject><subject>Lipids</subject><subject>Lipophilic</subject><subject>Lipophilicity</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Melanoma</subject><subject>Mice</subject><subject>mRNA</subject><subject>nanoparticle</subject><subject>Nanoparticles</subject><subject>Nanoparticles - chemistry</subject><subject>Nucleic acids</subject><subject>Physical Sciences</subject><subject>Polymers</subject><subject>Polymers - chemistry</subject><subject>RNA, Messenger - genetics</subject><subject>Self-assembly</subject><subject>Spleen</subject><subject>Structure-function relationships</subject><subject>Toll-like receptors</subject><subject>Transfection</subject><subject>Vaccination</subject><subject>vaccine</subject><subject>Vaccines</subject><issn>0027-8424</issn><issn>1091-6490</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNqFks1v1DAQxSMEoqVw5oYiceFA2rEdJ_YJLeVTqkBCwNVy7EnqymundlLUI_85Xm0plAsnjzS_9-SZeVX1lMAxgZ6dzEHnY8qAdNARCveqQwKSNF0r4X51CED7RrS0Page5XwBAJILeFgdsJ4xSQk5rH6-dtHilLTVg8fauznO5847U8_RX28xlWr75dOmDjrEWafFGY-5HmMq7KSDbcaEWC86Tbi4MNVxrPPsMRSdxWCTK4raoPd7kdHBYKqvtDEu6MXF8Lh6MGqf8cnNe1R9e_f26-mH5uzz-4-nm7PGtLJfmkFyKXsuje6sZbRFCpZro0cuLeMMTF863BhqcRhEOxBOOxhRDMIIIThnR9XLvW_-gfM6qDm5rU7XKmqn3rjvGxXTpNZVcZBtu8Ob_-PerYoCl4IV_tWeL_AWrcGwJO3vyO52gjtXU7xSBKhkAmRxeHHjkOLlinlRW5d3m9MB45oVFVSwjvYECvr8H_QirimU9RWKlSuTvu0LdbKnTIo5Jxxvf0NA7eKjdvFRf-JTFM_-HuKW_50X9guZ9cSy</recordid><startdate>20230627</startdate><enddate>20230627</enddate><creator>Ben-Akiva, Elana</creator><creator>Karlsson, Johan</creator><creator>Hemmati, Shayan</creator><creator>Yu, Hongzhe</creator><creator>Tzeng, Stephany Y</creator><creator>Pardoll, Drew M</creator><creator>Green, Jordan J</creator><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>DG8</scope><scope>ACNBI</scope><scope>D8T</scope><scope>DF2</scope><scope>ZZAVC</scope><orcidid>https://orcid.org/0000-0003-4176-3808</orcidid><orcidid>https://orcid.org/0000-0001-6008-6692</orcidid><orcidid>https://orcid.org/0000-0003-1085-5902</orcidid></search><sort><creationdate>20230627</creationdate><title>Biodegradable lipophilic polymeric mRNA nanoparticles for ligand-free targeting of splenic dendritic cells for cancer vaccination</title><author>Ben-Akiva, Elana ; 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To advance this technology requires delivery formulations for efficient intracellular delivery to antigen-presenting cells. We developed a class of bioreducible lipophilic poly(beta-amino ester) nanocarriers with quadpolymer architecture. The platform is agnostic to the mRNA sequence, with one-step self-assembly allowing for delivery of multiple antigen-encoding mRNAs as well as codelivery of nucleic acid-based adjuvants. We examined structure-function relationships for NP-mediated mRNA delivery to dendritic cells (DCs) and identified that a lipid subunit of the polymer structure was critical. Following intravenous administration, the engineered NP design facilitated targeted delivery to the spleen and preferential transfection of DCs without the need for surface functionalization with targeting ligands. 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| subjects | Adenocarcinoma Adenocarcinoma - pathology Adjuvants Adjuvants, Immunologic Animal models Animals Antigen-presenting cells Antigens Biodegradation Biological Sciences Cancer Cancer therapies Cancer Vaccines CD8 antigen Colonic Neoplasms - pathology Colonic Neoplasms - therapy delivery Dendritic Cells Humans Intravenous administration Ligands Lipids Lipophilic Lipophilicity Lymphocytes Lymphocytes T Melanoma Mice mRNA nanoparticle Nanoparticles Nanoparticles - chemistry Nucleic acids Physical Sciences Polymers Polymers - chemistry RNA, Messenger - genetics Self-assembly Spleen Structure-function relationships Toll-like receptors Transfection Vaccination vaccine Vaccines |
| title | Biodegradable lipophilic polymeric mRNA nanoparticles for ligand-free targeting of splenic dendritic cells for cancer vaccination |
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