{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:44:40Z","timestamp":1792806280847,"version":"4.5.0"},"reference-count":60,"publisher":"National Academy of Sciences","issue":"7","license":[{"start":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T00:00:00Z","timestamp":1707091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL153539"],"award-info":[{"award-number":["R01HL153539"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL164350"],"award-info":[{"award-number":["R01HL164350"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000052","name":"HHS | NIH | NIH Office of the Director","doi-asserted-by":"publisher","award":["DP2 TR002776"],"award-info":[{"award-number":["DP2 TR002776"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000861","name":"Burroughs Wellcome Fund","doi-asserted-by":"publisher","award":["Career Award at the Scientific Interface"],"award-info":[{"award-number":["Career Award at the Scientific Interface"]}],"id":[{"id":"10.13039\/100000861","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["CBET-2145491"],"award-info":[{"award-number":["CBET-2145491"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,2,13]]},"abstract":"<jats:p>Macrophages are integral components of the innate immune system, playing a dual role in host defense during infection and pathophysiological states. Macrophages contribute to immune responses and aid in combatting various infections, yet their production of abundant proinflammatory cytokines can lead to uncontrolled inflammation and worsened tissue damage. Therefore, reducing macrophage-derived proinflammatory cytokine release represents a promising approach for treating various acute and chronic inflammatory disorders. However, limited macrophage-specific delivery vehicles have hindered the development of macrophage-targeted therapies. In this study, we screened a pool of 112 lipid nanoparticles (LNPs) to identify an optimal LNP formulation for efficient siRNA delivery. Subsequently, by conjugating the macrophage-specific antibody F4\/80 to the LNP surface, we constructed MacLNP, an enhanced LNP formulation designed for targeted macrophage delivery. In both in vitro and in vivo experiments, MacLNP demonstrated a significant enhancement in targeting macrophages. Specifically, delivery of siRNA targeting TAK1, a critical kinase upstream of multiple inflammatory pathways, effectively suppressed the phosphorylation\/activation of NF-kB. LNP-mediated inhibition of NF-kB, a key upstream regulator in the classic inflammatory signaling pathway, in the murine macrophage cell line RAW264.7 significantly reduced the release of proinflammatory cytokines after stimulation with the viral RNA mimic Poly(I:C). Finally, intranasal administration of MacLNP-encapsulated TAK1 siRNA markedly ameliorated lung injury induced by influenza infection. In conclusion, our findings validate the potential of targeted macrophage interventions in attenuating inflammatory responses, reinforcing the potential of LNP-mediated macrophage targeting to treat pulmonary inflammatory disorders.<\/jats:p>","DOI":"10.1073\/pnas.2314747121","type":"journal-article","created":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T15:09:16Z","timestamp":1707145756000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":80,"title":["Precision treatment of viral pneumonia through macrophage-targeted lipid nanoparticle delivery"],"prefix":"10.1073","volume":"121","author":[{"given":"Gan","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Penn-Children\u2019s Hospital of Philadelphia Lung Biology Institute, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5719-1336","authenticated-orcid":false,"given":"Lulu","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6455-8183","authenticated-orcid":false,"given":"Hannah C.","family":"Geisler","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0725-8111","authenticated-orcid":false,"given":"Junchao","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyuan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Penn-Children\u2019s Hospital of Philadelphia Lung Biology Institute, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3628-2244","authenticated-orcid":false,"given":"Michael J.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5740-643X","authenticated-orcid":false,"given":"Andrew E.","family":"Vaughan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Penn-Children\u2019s Hospital of Philadelphia Lung Biology Institute, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,2,5]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.02.015"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI124615"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-021-00629-x"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2020.102537"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2018-0294OC"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1402"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nnano.2014.84"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41578-021-00358-0"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2014.04.021"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.2174\/1389450115666141114152713"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/smll.200600139"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.nanolett.2c04479"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2116271119"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-021-00786-x"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41565-020-0669-6"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2015.05.261"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-800148-6.00004-3"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2013.04.018"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2021.08.009"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2012.06.007"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/celldisc.2017.23"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/smll.201805097"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.nanolett.0c00596"},{"key":"e_1_3_4_24_2","first-page":"2","article-title":"Chemistry of lipid nanoparticles for RNA delivery published as part of the accounts of chemical research special issue \u201cmRNA Therapeutics\u201d","volume":"55","author":"Sahay G.","year":"2022","unstructured":"G. Sahay, Y. Eygeris, M. Gupta, J. Kim, Chemistry of lipid nanoparticles for RNA delivery published as part of the accounts of chemical research special issue \u201cmRNA Therapeutics\u201d. Accounts Chem. Res. 55, 2\u201312 (2022).","journal-title":"Accounts Chem. Res."},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/smsc.202200071"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1602"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.nanolett.1c01353"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5277"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-01007-w"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1039\/D3TB00303E"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27493-0"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.2c02706"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abf4398"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1039\/D2RA02771B"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abm0594"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41565-017-0043-5"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41578-022-00529-7"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-022-01491-z"},{"key":"e_1_3_4_39_2","doi-asserted-by":"crossref","unstructured":"G. Zhao Vascular endothelial-derived SPARCL1 exacerbates viral pneumonia through pro-inflammatory macrophage activation. BioRxiv [Preprint] (2023). https:\/\/doi.org\/10.1101\/2023.05.25.541966 (Accessed 8 January 2023).","DOI":"10.1101\/2023.05.25.541966"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.ade0385"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1080\/15476286.2020.1730081"},{"key":"e_1_3_4_42_2","doi-asserted-by":"crossref","unstructured":"J. Nong Targeting lipid nanoparticles to the blood brain barrier to ameliorate acute ischemic stroke. BioRxiv [Preprint] (2023). https:\/\/doi.org\/10.1101\/2023.06.12.544645 (Accessed 8 January 2023).","DOI":"10.1161\/circ.148.suppl_1.16198"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0331-4"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.12703\/P6-13"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20081056"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri910"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2011.00065"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.103479"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2021.12.027"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109092"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.26429"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-022516-034339"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1115635109"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2021.03.003"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41565-019-0591-y"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41578-021-00358-0"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27493-0"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41565-020-0669-6"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.nanolett.8b02917"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00018.2011"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2314747121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T15:11:06Z","timestamp":1707145866000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2314747121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,5]]},"references-count":60,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2024,2,13]]}},"alternative-id":["10.1073\/pnas.2314747121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2314747121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,5]]},"assertion":[{"value":"2023-08-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-01-05","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-02-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2314747121"}}