{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T16:34:14Z","timestamp":1786466054335,"version":"build-2736575974"},"reference-count":39,"publisher":"American Chemical Society (ACS)","issue":"31","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100002338","name":"Ministry of Education of the People's Republic of China","doi-asserted-by":"publisher","award":["JYB2025XDXM609"],"award-info":[{"award-number":["JYB2025XDXM609"]}],"id":[{"id":"10.13039\/501100002338","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2025M773518"],"award-info":[{"award-number":["2025M773518"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005089","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","award":["Z240028"],"award-info":[{"award-number":["Z240028"]}],"id":[{"id":"10.13039\/501100005089","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82225044"],"award-info":[{"award-number":["82225044"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82504688"],"award-info":[{"award-number":["82504688"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82522084"],"award-info":[{"award-number":["82522084"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82530110"],"award-info":[{"award-number":["82530110"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005090","name":"Beijing Nova Program","doi-asserted-by":"publisher","award":["20250484828"],"award-info":[{"award-number":["20250484828"]}],"id":[{"id":"10.13039\/501100005090","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Peking University Medicine plus X Pilot Program-Key Technologies Research and Development Project","award":["2024YXXLHGG001"],"award-info":[{"award-number":["2024YXXLHGG001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Pulmonary delivery of lipid nanoparticle (LNP)-based mRNA vaccines offers a promising strategy for localized lung cancer immunotherapy, yet how distinct pulmonary administration routes determine cellular targeting and therapeutic efficacy remains poorly understood. Here, we systematically evaluate intranasal and intratracheal delivery of mRNA-LNP vaccines and reveal a route-dependent immunological mechanism governing lung-targeted tumor vaccination. Although intratracheal administration yields only a 2.6-fold increase in total pulmonary protein expression compared to intranasal delivery, it produces a striking 26.8-fold enhancement in functional mRNA transfection efficiency within alveolar macrophages, the dominant antigen-presenting cell population in the alveolar space. This selective targeting reprograms alveolar macrophages toward an activated antigen-presenting phenotype, promoting efficient antigen presentation, robust CD8+ T-cell responses, and superior prophylactic and therapeutic efficacy in pulmonary tumor models. Notably, local depletion of alveolar macrophages completely abolishes the antitumor protection conferred by intratracheal vaccination, establishing their indispensable role in mediating pulmonary mRNA vaccine efficacy. Together, these findings provide mechanistic insights into lung-targeted mRNA cancer vaccination driven by alveolar macrophage engagement, providing critical insights for the design of next-generation LNP-based nanomedicines for lung cancer immunotherapy.<\/jats:p>","DOI":"10.1021\/acsnano.6c04529","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T14:02:28Z","timestamp":1785852148000},"page":"21798-21811","source":"Crossref","is-referenced-by-count":0,"title":["Intratracheal Delivery\nof mRNA Lipid Nanoparticles\nReprograms Alveolar Macrophages for Pulmonary Cancer Immunotherapy"],"prefix":"10.1021","volume":"20","author":[{"given":"Jiayi","family":"Zhou","sequence":"first","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100191"]},{"name":"Peking University , , ,","place":["Beijing, China, 100191"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanzhuoyi","family":"Li","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100191"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100191"]},{"name":"Peking University , , ,","place":["Beijing, China, 100191"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panshuang","family":"Qiao","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100191"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100191"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihan","family":"Ding","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100191"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilei","family":"Lu","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100191"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiongran","family":"Yu","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100191"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Ding","sequence":"additional","affiliation":[{"name":"Peking University People\u2019s Hospital , , ,","place":["Beijing, China, 100044"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Chen","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100191"]},{"name":"Peking University , , ,","place":["Beijing, China, 100191"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dezhong","family":"Ji","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100191"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1676-4211","authenticated-orcid":true,"given":"Yiguang","family":"Wang","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100191"]},{"name":"Peking University , , ,","place":["Beijing, China, 100191"]},{"name":"Peking University , , ,","place":["Beijing, China, 100191"]},{"name":"Peking University , , ,","place":["Ningbo, China, 315832"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9529-2522","authenticated-orcid":true,"given":"Binlong","family":"Chen","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100191"]},{"name":"Peking University , , ,","place":["Beijing, China, 100191"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"issue":"1","key":"2026081111120456300_cit1","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1038\/s41392-025-02243-6","article-title":"Advances in Molecular\nPathology and Therapy of Non-Small Cell Lung Cancer","volume":"10","author":"Huang","year":"2025","journal-title":"Signal Transduction Targeted Ther."},{"key":"2026081111120456300_cit2","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1038\/s41571-023-00798-3","article-title":"The Global\nBurden of Lung Cancer:\nCurrent Status and Future Trends","volume":"20","author":"Leiter","year":"2023","journal-title":"Nat. Rev.\nClin. Oncol."},{"key":"2026081111120456300_cit3","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1038\/s43018-025-00992-5","article-title":"The Current and Emerging\nImmunotherapy Paradigm in Small-Cell Lung Cancer","volume":"6","author":"Qin","year":"2025","journal-title":"Nat. Cancer"},{"key":"2026081111120456300_cit4","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1038\/s41573-024-00977-6","article-title":"The 60-Year Evolution of Lipid Nanoparticles for Nucleic\nAcid Delivery","volume":"23","author":"Cullis","year":"2024","journal-title":"Nat. Rev. Drug Discovery"},{"issue":"27","key":"2026081111120456300_cit5","doi-asserted-by":"publisher","first-page":"2603","DOI":"10.1056\/NEJMoa2034577","article-title":"Safety\nand Efficacy\nof the BNT162b2 mRNA Covid-19 Vaccine","volume":"383","author":"Polack","year":"2020","journal-title":"N. Engl.\nJ. Med."},{"key":"2026081111120456300_cit6","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1056\/NEJMoa2035389","article-title":"Efficacy\nand Safety of the mRNA-1273 SARS-CoV-2 Vaccine","volume":"384","author":"Baden","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"2026081111120456300_cit7","doi-asserted-by":"publisher","first-page":"1943","DOI":"10.1016\/j.apsb.2025.11.023","article-title":"Deciphering the Biological Fate of\nmRNA-LNP-Based Biologics: A Perspective from Tissue to Intracellular\nDistribution","volume":"16","author":"Xu","year":"2026","journal-title":"Acta Pharm. Sin. B"},{"issue":"12","key":"2026081111120456300_cit8","doi-asserted-by":"publisher","first-page":"103479","DOI":"10.1016\/j.isci.2021.103479","article-title":"The mRNA-LNP\nplatform\u2019s lipid\nnanoparticle component used in preclinical vaccine studies is highly\ninflammatory","volume":"24","author":"Ndeupen","year":"2021","journal-title":"iScience"},{"key":"2026081111120456300_cit9","doi-asserted-by":"publisher","first-page":"1332","DOI":"10.1056\/NEJMc2109975","article-title":"Myocarditis After\nCOVID-19 mRNA Vaccination","volume":"385","author":"Verma","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"2026081111120456300_cit10","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1007\/s11095-021-03015-x","article-title":"Nanoparticle-Mediated\nCytoplasmic Delivery of Messenger RNA Vaccines:\nChallenges and Future Perspectives","volume":"38","author":"Wu","year":"2021","journal-title":"Pharm. 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Controlled Release"},{"key":"2026081111120456300_cit12","doi-asserted-by":"publisher","first-page":"14792","DOI":"10.1021\/acsnano.2c05647","article-title":"Engineering\nLipid Nanoparticles for Enhanced Intracellular Delivery of mRNA through\nInhalation","volume":"16","author":"Kim","year":"2022","journal-title":"ACS Nano"},{"issue":"1","key":"2026081111120456300_cit13","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/s41392-025-02191-1","article-title":"Intranasal Prime-Boost\nRNA Vaccination Elicits Potent T Cell Response\nfor Lung Cancer Therapy","volume":"10","author":"Li","year":"2025","journal-title":"Signal Transduction\nTargeted Ther."},{"key":"2026081111120456300_cit14","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1007\/s13346-020-00891-5","article-title":"Intranasal\nDrug Delivery: Opportunities\nand Toxicologic Challenges during Drug Development","volume":"12","author":"Keller","year":"2022","journal-title":"Drug Delivery Transl. Res."},{"key":"2026081111120456300_cit15","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1093\/toxsci\/55.1.24","article-title":"Intratracheal\nInstillation as an Exposure Technique for the Evaluation of Respiratory\nTract Toxicity: Uses and Limitations","volume":"55","author":"Driscoll","year":"2000","journal-title":"Toxicol.\nSci."},{"key":"2026081111120456300_cit16","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1038\/s41586-020-2798-3","article-title":"SARS-CoV-2\nVaccines in Development","volume":"586","author":"Krammer","year":"2020","journal-title":"Nature"},{"issue":"2","key":"2026081111120456300_cit17","doi-asserted-by":"publisher","first-page":"102547","DOI":"10.1016\/j.omtn.2025.102547","article-title":"Deconvolution\nof Cargo Delivery and Immunogenicity following Intranasal Delivery\nof mRNA Lipid Nanoparticle Vaccines","volume":"36","author":"Vu","year":"2025","journal-title":"Mol. Ther.\u2013Nucleic\nAcids"},{"key":"2026081111120456300_cit18","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1038\/s41586-023-06951-3","article-title":"Mucosal Boosting Enhances Vaccine Protection\nagainst SARS-CoV-2 in Macaques","volume":"626","author":"McMahan","year":"2024","journal-title":"Nature"},{"key":"2026081111120456300_cit19","doi-asserted-by":"publisher","first-page":"1913","DOI":"10.1038\/s41590-024-01951-5","article-title":"Mucosal\nAdenovirus Vaccine Boosting Elicits IgA and\nDurably Prevents XBB.1.16 Infection in Nonhuman Primates","volume":"25","author":"Gagne","year":"2024","journal-title":"Nat. Immunol."},{"issue":"6","key":"2026081111120456300_cit20","doi-asserted-by":"publisher","first-page":"112721","DOI":"10.1016\/j.isci.2025.112721","article-title":"Mucosal\nBoosting Increases\nProtective Efficacy of an Influenza Vaccine in Mice","volume":"28","author":"Wang","year":"2025","journal-title":"iScience"},{"key":"2026081111120456300_cit21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.immuni.2013.07.012","article-title":"Oncology Meets Immunology:\nThe Cancer-Immunity Cycle","volume":"39","author":"Chen","year":"2013","journal-title":"Immunity"},{"issue":"10","key":"2026081111120456300_cit22","doi-asserted-by":"publisher","first-page":"2231","DOI":"10.1016\/j.immuni.2023.09.005","article-title":"CD8+ T Cells in\nthe Cancer-Immunity Cycle","volume":"56","author":"Giles","year":"2023","journal-title":"Immunity"},{"key":"2026081111120456300_cit23","doi-asserted-by":"publisher","first-page":"7300","DOI":"10.1021\/acs.nanolett.5b02497","article-title":"Optimization\nof Lipid Nanoparticle Formulations for mRNA Delivery in Vivo with\nFractional Factorial and Definitive Screening Designs","volume":"15","author":"Kauffman","year":"2015","journal-title":"Nano Lett."},{"key":"2026081111120456300_cit24","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1038\/s41565-023-01548-3","article-title":"Combinatorial Development\nof Nebulized mRNA Delivery\nFormulations for the Lungs","volume":"19","author":"Jiang","year":"2024","journal-title":"Nat. Nanotechnol."},{"key":"2026081111120456300_cit25","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1038\/nature07005","article-title":"The Branching Programme\nof Mouse Lung Development","volume":"453","author":"Metzger","year":"2008","journal-title":"Nature"},{"key":"2026081111120456300_cit26","doi-asserted-by":"publisher","first-page":"2009","DOI":"10.1038\/s41587-024-02528-1","article-title":"Nanocarrier\nImaging\nat Single-Cell Resolution Across Entire Mouse Bodies with Deep Learning","volume":"43","author":"Luo","year":"2025","journal-title":"Nat. Biotechnol."},{"issue":"52","key":"2026081111120456300_cit27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2109256118","article-title":"On the Mechanism\nof Tissue-Specific\nmRNA Delivery by Selective Organ Targeting Nanoparticles","volume":"118","author":"Dilliard","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026081111120456300_cit28","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e37221","article-title":"Optimized\nMethod for Higher Yield of Alveolar Macrophage Isolation for Ex Vivo Studies","volume":"10","author":"Devkota","year":"2024","journal-title":"Heliyon"},{"key":"2026081111120456300_cit29","doi-asserted-by":"publisher","first-page":"1758","DOI":"10.1038\/s41416-024-02671-1","article-title":"Cancer-Associated\nFibroblasts Expressing Fibroblast\nActivation Protein and Podoplanin in Non-Small Cell Lung Cancer Predict\nPoor Clinical Outcome","volume":"130","author":"Mathieson","year":"2024","journal-title":"Br. J. Cancer"},{"issue":"1","key":"2026081111120456300_cit30","doi-asserted-by":"publisher","first-page":"4587","DOI":"10.1038\/s41467-022-32255-7","article-title":"Temporal\nProfiling of the Breast Tumour Microenvironment\nReveals Collagen XII as a Driver of Metastasis","volume":"13","author":"Papanicolaou","year":"2022","journal-title":"Nat. Commun."},{"issue":"1","key":"2026081111120456300_cit31","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1186\/s12974-020-01931-0","article-title":"Effects of Long-Term\nand Brain-Wide Colonization of\nPeripheral Bone Marrow-Derived Myeloid Cells in the CNS","volume":"17","author":"Hohsfield","year":"2020","journal-title":"J. Neuroinflammation"},{"key":"2026081111120456300_cit32","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1038\/s41565-020-0669-6","article-title":"Selective\nOrgan Targeting (SORT) Nanoparticles for Tissue-Specific mRNA Delivery\nand CRISPR\u2013Cas Gene Editing","volume":"15","author":"Cheng","year":"2020","journal-title":"Nat. Nanotechnol."},{"key":"2026081111120456300_cit33","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/j.jconrel.2023.09.031","article-title":"Spray Dried Lipid Nanoparticle\nFormulations Enable Intratracheal Delivery of mRNA","volume":"363","author":"Friis","year":"2023","journal-title":"J. Controlled Release"},{"issue":"38","key":"2026081111120456300_cit34","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adh1655","article-title":"Intranasal mRNA-LNP Vaccination Protects Hamsters\nfrom SARS-CoV-2 Infection","volume":"9","author":"Baldeon Vaca","year":"2023","journal-title":"Sci. Adv."},{"key":"2026081111120456300_cit35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41563-026-02555-0","article-title":"Amino\nAcid-Derived Ionizable Lipids Enable Inhaled Base Editing for\nTherapeutic Gene Correction in the Lung","author":"Gong","year":"2026","journal-title":"Nat.\nMater."},{"issue":"19","key":"2026081111120456300_cit36","doi-asserted-by":"publisher","DOI":"10.1172\/JCI170501","article-title":"Alveolar Macrophages\nin Tissue Homeostasis, Inflammation, and Infection: Evolving Concepts\nof Therapeutic Targeting","volume":"133","author":"Malainou","year":"2023","journal-title":"J. Clin. Invest."},{"issue":"6800","key":"2026081111120456300_cit37","doi-asserted-by":"publisher","DOI":"10.1126\/science.aea1260","article-title":"Mucosal Vaccination\nin Mice Provides Protection\nfrom Diverse Respiratory Threats","volume":"392","author":"Zhang","year":"2026","journal-title":"Science"},{"key":"2026081111120456300_cit38","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/978-1-4615-2930-9_51","article-title":"Migration of Alveolar Macrophages\nfrom Alveolar Space to Paracortical T Cell Area of the Draining Lymph\nNode","volume-title":"Dendritic Cells in Fundamental and\nClinical Immunology","author":"Claassen","year":"1993"},{"key":"2026081111120456300_cit39","doi-asserted-by":"publisher","first-page":"111828","DOI":"10.1016\/j.celrep.2022.111828","article-title":"Alveolar Macrophages Instruct CD8+\nT-Cell Expansion by Antigen Cross-Presentation in Lung","volume":"41","author":"Kawasaki","year":"2022","journal-title":"Cell Rep."}],"container-title":["ACS Nano"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsnano.6c04529","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/ancac3\/article-pdf\/20\/31\/21798\/66345491\/acsnano.6c04529.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/ancac3\/article-pdf\/20\/31\/21798\/66345491\/acsnano.6c04529.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T15:29:56Z","timestamp":1786462196000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/ancac3\/article\/20\/31\/21798\/5237572\/Intratracheal-Delivery-of-mRNA-Lipid-Nanoparticles"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,31]]},"references-count":39,"journal-issue":{"issue":"31","published-online":{"date-parts":[[2026,7,31]]},"published-print":{"date-parts":[[2026,8,11]]}},"URL":"https:\/\/doi.org\/10.1021\/acsnano.6c04529","relation":{},"ISSN":["1936-0851","1936-086X"],"issn-type":[{"value":"1936-0851","type":"print"},{"value":"1936-086X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,31]]}}}