{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T18:28:13Z","timestamp":1790015293551,"version":"4.0.1"},"reference-count":51,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T00:00:00Z","timestamp":1711929600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T00:00:00Z","timestamp":1711929600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T00:00:00Z","timestamp":1711929600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T00:00:00Z","timestamp":1711929600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T00:00:00Z","timestamp":1711929600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T00:00:00Z","timestamp":1711929600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T00:00:00Z","timestamp":1711929600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Journal of Controlled Release"],"published-print":{"date-parts":[[2024,4]]},"DOI":"10.1016\/j.jconrel.2024.03.016","type":"journal-article","created":{"date-parts":[[2024,3,18]],"date-time":"2024-03-18T16:04:04Z","timestamp":1710777844000},"page":"663-675","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":40,"special_numbering":"C","title":["Tumor-activated IL-2 mRNA delivered by lipid nanoparticles for cancer immunotherapy"],"prefix":"10.1016","volume":"368","author":[{"given":"Yuhao","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenliang","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinsong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.jconrel.2024.03.016_bb0005","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.immuni.2013.07.012","article-title":"Oncology meets immunology: the Cancer-immunity cycle","volume":"39","author":"Chen","year":"2013","journal-title":"Immunity"},{"key":"10.1016\/j.jconrel.2024.03.016_bb0010","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/s41591-018-0014-x","article-title":"Understanding the tumor immune microenvironment (TIME) for effective therapy","volume":"24","author":"Binnewies","year":"2018","journal-title":"Nat. Med."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0015","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1126\/science.aaa4967","article-title":"Adoptive cell transfer as personalized immunotherapy for human cancer","volume":"348","author":"Rosenberg","year":"2015","journal-title":"Science"},{"key":"10.1016\/j.jconrel.2024.03.016_bb0020","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/32588","article-title":"Dendritic cells and the control of immunity","volume":"392","author":"Banchereau","year":"1998","journal-title":"Nature"},{"key":"10.1016\/j.jconrel.2024.03.016_bb0025","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.cytogfr.2007.01.014","article-title":"Cytokine gene transfer for cancer therapy","volume":"18","author":"Podhajcer","year":"2007","journal-title":"Cytokine Growth Factor Rev."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0030","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1038\/nrc3245","article-title":"The immune contexture in human tumours: impact on clinical outcome","volume":"12","author":"Fridman","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"10.1016\/j.jconrel.2024.03.016_bb0035","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/S0140-6736(00)04046-0","article-title":"Inflammation and cancer: back to Virchow?","volume":"357","author":"Balkwill","year":"2001","journal-title":"Lancet"},{"key":"10.1016\/j.jconrel.2024.03.016_bb0040","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1038\/nri1901","article-title":"The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design","volume":"6","author":"Waldmann","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0045","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1146\/annurev.immunol.26.021607.090357","article-title":"The biology of interleukin-2","volume":"26","author":"Matek","year":"2008","journal-title":"Annu. Rev. Immunol."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0050","first-page":"S70","article-title":"High dose aldesleukin in renal cell carcinoma: long term survival update, Cancer journal from","volume":"3","author":"Fisher","year":"1997","journal-title":"Sci. Am."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0055","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1200\/JCO.1999.17.7.2105","article-title":"High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993","volume":"17","author":"Atkins","year":"1999","journal-title":"J. Clin. Oncol."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0060","doi-asserted-by":"crossref","first-page":"7440","DOI":"10.1158\/1078-0432.CCR-11-1650","article-title":"Molecular insights on the peripheral and Intratumoral effects of systemic high-dose rIL-2 (Aldesleukin) Administration for the Treatment of metastatic melanoma","volume":"17","author":"Weiss","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0065","doi-asserted-by":"crossref","first-page":"1218082","DOI":"10.3389\/fimmu.2023.1218082","article-title":"Engineering cytokines for cancer immunotherapy: a systematic review","volume":"14","author":"Fu","year":"2023","journal-title":"Front. Immunol."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0070","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1158\/2159-8290.CD-18-1495","article-title":"A first-in-human study and biomarker analysis of NKTR-214, a Novel 1L2R beta gamma-biased cytokine, in patients with advanced or metastatic solid tumors","volume":"9","author":"Bentebibel","year":"2019","journal-title":"Cancer Discovery"},{"key":"10.1016\/j.jconrel.2024.03.016_bb0075","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1158\/1078-0432.CCR-15-1631","article-title":"NKTR-214, an engineered cytokine with biased IL2 receptor binding, increased tumor exposure, and marked efficacy in mouse tumor models","volume":"22","author":"Charych","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0080","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1136\/jitc-2020-000673","article-title":"ALKS 4230: a novel engineered IL-2 fusion protein with an improved cellular selectivity profile for cancer immunotherapy","volume":"8","author":"Lopes","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"10.1016\/j.jconrel.2024.03.016_bb0085","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.immuni.2013.01.004","article-title":"Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy","volume":"38","author":"Liao","year":"2013","journal-title":"Immunity"},{"key":"10.1016\/j.jconrel.2024.03.016_bb0090","doi-asserted-by":"crossref","first-page":"173-+","DOI":"10.1038\/s41586-022-05257-0","article-title":"PD-1 combination therapy with IL-2 modifies CD8(+) T cell exhaustion program","volume":"610","author":"Hashimoto","year":"2022","journal-title":"Nature"},{"key":"10.1016\/j.jconrel.2024.03.016_bb0095","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1158\/2326-6066.CIR-21-0831","article-title":"Discovery of a conditionally activated IL-2 that promotes antitumor immunity and induces tumor regression","volume":"10","author":"Nirschl","year":"2022","journal-title":"Cancer Immunol. Res."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0100","doi-asserted-by":"crossref","first-page":"7454","DOI":"10.1039\/D3TB00303E","article-title":"Enhanced immunogenicity induced by mRNA vaccines with various lipid nanoparticles as carriers for SARS-CoV-2 infection","volume":"11","author":"Zhang","year":"2023","journal-title":"J. Mater. Chem. B"},{"key":"10.1016\/j.jconrel.2024.03.016_bb0105","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1056\/NEJMoa2035389","article-title":"Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine","volume":"384","author":"Baden","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0110","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.cell.2021.12.033","article-title":"Balazs, mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 omicron variant","volume":"185","author":"Garcia-Beltran","year":"2022","journal-title":"Cell"},{"key":"10.1016\/j.jconrel.2024.03.016_bb0115","doi-asserted-by":"crossref","DOI":"10.1200\/JCO.2019.37.15_suppl.2523","article-title":"A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors","volume":"37","author":"Burris","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0120","doi-asserted-by":"crossref","first-page":"E450","DOI":"10.1016\/S1470-2045(22)00372-2","article-title":"Clinical advances and ongoing trials of mRNA vaccines for cancer treatment","volume":"23","author":"Lorentzen","year":"2022","journal-title":"Lancet Oncol."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0125","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.jconrel.2022.03.021","article-title":"Intratumoral delivery of IL-12 and IL-27 mRNA using lipid nanoparticles for cancer immunotherapy","volume":"345","author":"Liu","year":"2022","journal-title":"J. Control. Release"},{"key":"10.1016\/j.jconrel.2024.03.016_bb0130","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1038\/s41568-023-00586-2","article-title":"mRNA-based cancer therapeutics","volume":"23","author":"Liu","year":"2023","journal-title":"Nat. Rev. Cancer"},{"key":"10.1016\/j.jconrel.2024.03.016_bb0135","doi-asserted-by":"crossref","first-page":"120586","DOI":"10.1016\/j.ijpharm.2021.120586","article-title":"mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability","volume":"601","author":"Schoenmaker","year":"2021","journal-title":"Int. J. Pharm."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0140","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1038\/s41578-021-00358-0","article-title":"Lipid nanoparticles for mRNA delivery","volume":"6","author":"Hou","year":"2021","journal-title":"Nat. Rev. Materials"},{"key":"10.1016\/j.jconrel.2024.03.016_bb0145","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1016\/j.ymthe.2017.03.013","article-title":"Lipid nanoparticle Systems for Enabling Gene Therapies","volume":"25","author":"Cullis","year":"2017","journal-title":"Mol. Ther."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0150","doi-asserted-by":"crossref","first-page":"7233","DOI":"10.1038\/s41467-021-27493-0","article-title":"An ionizable lipid toolbox for RNA delivery","volume":"12","author":"Han","year":"2021","journal-title":"Nat. Commun."},{"issue":"4","key":"10.1016\/j.jconrel.2024.03.016_bb0155","doi-asserted-by":"crossref","first-page":"2294","DOI":"10.1021\/jacs.2c10670","article-title":"Iterative Design of Ionizable Lipids for intramuscular mRNA delivery","volume":"145","author":"Tilstra","year":"2023","journal-title":"J. Am. Chem. Soc."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0160","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1038\/s41578-021-00358-0","article-title":"Lipid nanoparticles for mRNA delivery","volume":"6","author":"Hou","year":"2021","journal-title":"Nat. Rev. Mater."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0165","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2301067120","article-title":"Lipid nanoparticle topology regulates endosomal escape and delivery of RNA to the cytoplasm","volume":"120","author":"Zheng","year":"2023","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0170","doi-asserted-by":"crossref","DOI":"10.1083\/jcb.202110137","article-title":"Endosomal escape of delivered mRNA from endosomal recycling tubules visualized at the nanoscale","volume":"221","author":"Paramasivam","year":"2022","journal-title":"J. Cell Biol."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0175","first-page":"4289","article-title":"Illuminating endosomal escape of polymorphic lipid nanoparticles that boost mRNA delivery, biomaterials","volume":"9","author":"Herrera","year":"2021","journal-title":"Science"},{"key":"10.1016\/j.jconrel.2024.03.016_bb0180","doi-asserted-by":"crossref","first-page":"5711","DOI":"10.1021\/acs.nanolett.7b02664","article-title":"Boosting intracellular delivery of lipid nanoparticle-encapsulated mRNA","volume":"17","author":"Patel","year":"2017","journal-title":"Nano Lett."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0185","doi-asserted-by":"crossref","first-page":"eaaz6893","DOI":"10.1126\/sciadv.aaz6893","article-title":"Impact of mRNA chemistry and manufacturing process on innate immune activation","volume":"6","author":"Nelson","year":"2020","journal-title":"Sci. Adv."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0190","doi-asserted-by":"crossref","first-page":"6023","DOI":"10.1093\/nar\/gkx135","article-title":"N1-methyl-pseudouridine in mRNA enhances translation through eIF2 alpha-dependent and independent mechanisms by increasing ribosome density","volume":"45","author":"Svitkin","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0195","doi-asserted-by":"crossref","DOI":"10.1126\/sciimmunol.abi6899","article-title":"A tumor-specific pro-IL-12 activates preexisting cytotoxic T cells to control established tumors","volume":"7","author":"Xue","year":"2022","journal-title":"Sci. Immunol."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0200","doi-asserted-by":"crossref","first-page":"23788","DOI":"10.1074\/jbc.M111574200","article-title":"A unique substrate binding mode discriminates membrane type-1 matrix metalloproteinase from other matrix metalloproteinases","volume":"277","author":"Kridel","year":"2002","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0205","doi-asserted-by":"crossref","first-page":"2788","DOI":"10.1073\/pnas.0511161103","article-title":"Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor","volume":"103","author":"Stauber","year":"2006","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0210","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1126\/science.1117893","article-title":"Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gamma(c) receptors","volume":"310","author":"Wang","year":"2005","journal-title":"Science"},{"key":"10.1016\/j.jconrel.2024.03.016_bb0215","doi-asserted-by":"crossref","first-page":"1340-+","DOI":"10.1126\/science.abm4805","article-title":"Computed structures of core eukaryotic protein complexes","volume":"374","author":"Humphreys","year":"2021","journal-title":"Science"},{"key":"10.1016\/j.jconrel.2024.03.016_bb0220","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/0022-1759(93)90088-O","article-title":"AN IMPROVED MTT ASSAY","volume":"157","author":"Sladowski","year":"1993","journal-title":"J. Immunol. Methods"},{"key":"10.1016\/j.jconrel.2024.03.016_bb0225","doi-asserted-by":"crossref","first-page":"4935","DOI":"10.1073\/pnas.91.11.4935","article-title":"A LYMPHOKINE, provisionally designated interleukin-t and produced by A human adult t-cell leukemia line, stimulates t-cell proliferation and the induction of LYMPHOKINE-activated killer-cells","volume":"91","author":"Burton","year":"1994","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0230","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1111\/j.1365-2567.2011.03428.x","article-title":"Development of an attenuated interleukin-2 fusion protein that can be activated by tumour-expressed proteases","volume":"133","author":"Puskas","year":"2011","journal-title":"Immunology"},{"key":"10.1016\/j.jconrel.2024.03.016_bb0235","doi-asserted-by":"crossref","first-page":"E108","DOI":"10.1158\/0008-5472.CAN-17-0307","article-title":"TIMER: A web server for comprehensive analysis of tumor-infiltrating immune cells","volume":"77","author":"Li","year":"2017","journal-title":"Cancer Res."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0240","doi-asserted-by":"crossref","first-page":"W509","DOI":"10.1093\/nar\/gkaa407","article-title":"TIMER2.0 for analysis of tumor-infiltrating immune cells","volume":"48","author":"Li","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0245","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.coi.2007.02.004","article-title":"Regulatory T cells and cancer","volume":"19","author":"Wang","year":"2007","journal-title":"Curr. Opin. Immunol."},{"key":"10.1016\/j.jconrel.2024.03.016_bb0250","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.3390\/cells8121647","article-title":"Myeloid-derived suppressor cells: major figures that shape the immunosuppressive and Angiogenic network in Cancer","volume":"8","author":"Vetsika","year":"2019","journal-title":"Cells"},{"key":"10.1016\/j.jconrel.2024.03.016_bb0255","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1002\/ijc.25429","article-title":"Regulatory T cells in tumor immunity","volume":"127","author":"Nishikawa","year":"2010","journal-title":"Int. J. Cancer"}],"container-title":["Journal of Controlled Release"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0168365924001688?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0168365924001688?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T16:35:48Z","timestamp":1738082148000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0168365924001688"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4]]},"references-count":51,"alternative-id":["S0168365924001688"],"URL":"https:\/\/doi.org\/10.1016\/j.jconrel.2024.03.016","relation":{},"ISSN":["0168-3659"],"issn-type":[{"value":"0168-3659","type":"print"}],"subject":[],"published":{"date-parts":[[2024,4]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Tumor-activated IL-2 mRNA delivered by lipid nanoparticles for cancer immunotherapy","name":"articletitle","label":"Article Title"},{"value":"Journal of Controlled Release","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.jconrel.2024.03.016","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2024 Elsevier B.V. All rights reserved.","name":"copyright","label":"Copyright"}]}}