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One strategy to eradicate latent HIV is to activate viral transcription, followed by elimination of infected cells through virus-mediated cytotoxicity or immune-mediated clearance. We hypothesised that mRNA-lipid nanoparticle (LNP) technology would provide an opportunity to deliver mRNA encoding proteins able to reverse HIV latency in resting CD4<jats:sup>+<\/jats:sup> T cells. Here we develop an LNP formulation (LNP X) with unprecedented potency to deliver mRNA to hard-to-transfect resting CD4<jats:sup>+<\/jats:sup> T cells in the absence of cellular toxicity or activation. Encapsulating an mRNA encoding the HIV Tat protein, an activator of HIV transcription, LNP X enhances HIV transcription in ex vivo CD4<jats:sup>+<\/jats:sup> T cells from people living with HIV. LNP X further enables the delivery of clustered regularly interspaced short palindromic repeats (CRISPR) activation machinery to modulate both viral and host gene transcription. These findings offer potential for the development of a range of nucleic acid-based T cell therapeutics.<\/jats:p>","DOI":"10.1038\/s41467-025-60001-2","type":"journal-article","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T12:00:45Z","timestamp":1748520045000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Efficient mRNA delivery to resting T cells to reverse HIV latency"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4473-7904","authenticated-orcid":false,"given":"Paula M.","family":"Cevaal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanislav","family":"Kan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8503-8150","authenticated-orcid":false,"given":"Bridget M.","family":"Fisher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7948-3380","authenticated-orcid":false,"given":"Michael A.","family":"Moso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdalla","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4821-801X","authenticated-orcid":false,"given":"Kiho","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2215-2510","authenticated-orcid":false,"given":"Rory A.","family":"Shepherd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youry","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesslyn","family":"Ong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denzil L.","family":"Furtado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marvin","family":"Holz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4485-1726","authenticated-orcid":false,"given":"Damian F. 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She has received funding from Gilead and Merck for investigator-initiated research projects unrelated to the content of this manuscript. DLF and FC are scientific founders of and hold equity in Messenger Bio. Messenger Bio was paid to synthesise mRNA for 60% of the work presented in the manuscript. P.M.C. was supported by a donation from the J and M Wright Foundation. The donation supported salary to complete some of this work. B.M.F., M.A.M., R.A.S. were supported by an Australian Government Research Training Programme Scholarship. M.A.M. was further supported by an NHMRC Postgraduate Scholarship, Rowden White Scholarship and Elizabeth Mary Sweet Scholarship. K.T. was supported by a Melbourne Research Scholarship. P.M.C., S.K., B.M.F., M.A.M., M.F., M.R., J.S. and S.R.L. are named investigators on a patent related to this work (PCT\/AU2024\/050506). No other authors declare any competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"4979"}}