{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T16:01:57Z","timestamp":1790870517709,"version":"4.1.0"},"reference-count":79,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background\/Objectives: Systemic administration of recombinant cytokines for immunomodulation in cancer and chronic infection is limited by toxicity and poor spatial control. Messenger RNA (mRNA)-encoded cytokines offer a programmable alternative, but the immunological consequences of interferon-\u03b2 (IFN-\u03b2) mRNA delivery in primary human immune cells, and its compatibility with co-delivered antigen-encoding mRNA, remain incompletely defined. This study evaluated whether nucleoside-modified, mRNA-encoded human IFN-\u03b2 can function as a multifunctional immunomodulator with pro-apoptotic activity and timing-dependent immunostimulatory properties. Methods: N1-methylpseudouridine-modified IFN-\u03b2 mRNA was transfected into HEK293T and HepG2 cell lines and into primary human monocyte-derived dendritic cells (MDDCs) and M2-polarized macrophages (MDMs) using Lipofectamine MessengerMAX, with OVA mRNA as a non-adjuvant control. Apoptosis, interferon-stimulated CXCL10 secretion, activation marker expression, and cytokine profiles were assessed by flow cytometry, ELISA, Western blot, and cytometric bead array. Adjuvant activity was evaluated in MDDCs co-transfected with IFN-\u03b2 and antigen (EGFP or OVA) mRNA under four temporal delivery regimens. Results: IFN-\u03b2 mRNA induced time-dependent apoptosis, most pronounced in HepG2 cells, and CXCL10 secretion in both cell lines. In primary immune cells, IFN-\u03b2 mRNA activated MDDCs, increased pro-inflammatory cytokine secretion, and repolarized M2-like macrophages toward a pro-inflammatory phenotype. In co-transfection experiments, IFN-\u03b2 mRNA enhanced MDDC activation across regimens, but antigen expression was preserved only when antigen mRNA was delivered before IFN-\u03b2 mRNA. Conclusions: mRNA-encoded IFN-\u03b2 combines direct pro-apoptotic activity with programmable, timing-dependent immunostimulatory effects, supporting its development as a component of next-generation mRNA-based immunotherapies and vaccines.<\/jats:p>","DOI":"10.3390\/vaccines14090829","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T15:35:28Z","timestamp":1790868928000},"page":"829","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Timing-Dependent Immunostimulatory Activity of Human IFN-\u03b2 mRNA in Primary Human Myeloid Cells"],"prefix":"10.3390","volume":"14","author":[{"given":"Silvia","family":"Fraude-El Ghazi","sequence":"first","affiliation":[{"name":"Children\u2019s Hospital, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Jos\u00e9","family":"Limeres","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rocio","family":"Gambaro","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1097-1275","authenticated-orcid":false,"given":"Ana","family":"Pena Vaquero","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Prawitt","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"German","family":"Islan","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9755-9155","authenticated-orcid":false,"given":"Stephan","family":"Gehring","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3144-8794","authenticated-orcid":false,"given":"Maximiliano L.","family":"Cacicedo","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20847","DOI":"10.1073\/pnas.0906481106","article-title":"Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity","volume":"106","author":"Balsamo","year":"2009","journal-title":"Proc. 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