{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T14:55:26Z","timestamp":1793976926882,"version":"4.8.0"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:00:00Z","timestamp":1769731200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":33,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"DOI":"10.1038\/s41467-026-69017-8","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T11:34:57Z","timestamp":1769772897000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Engineered internal architecture of core-shell lipid nanoparticles promotes efficient mRNA endosomal release"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9176-7287","authenticated-orcid":false,"given":"Tianyao","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bohong","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxuan","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hu","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Weng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinghao","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyu","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1636-6336","authenticated-orcid":false,"given":"Xingfa","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8352-1327","authenticated-orcid":false,"given":"Lianpan","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daming","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8065-4634","authenticated-orcid":false,"given":"Yuhong","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,30]]},"reference":[{"key":"69017_CR1","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1016\/j.cell.2023.02.031","volume":"186","author":"TM Raimondo","year":"2023","unstructured":"Raimondo, T. M., Reed, K., Shi, D., Langer, R. & Anderson, D. G. Delivering the next generation of cancer immunotherapies with RNA. Cell 186, 1535\u20131540 (2023).","journal-title":"Cell"},{"key":"69017_CR2","doi-asserted-by":"publisher","first-page":"2806","DOI":"10.1016\/j.cell.2022.03.045","volume":"185","author":"A Raguram","year":"2022","unstructured":"Raguram, A., Banskota, S. & Liu, D. R. Therapeutic in vivo delivery of gene editing agents. Cell 185, 2806\u20132827 (2022).","journal-title":"Cell"},{"key":"69017_CR3","doi-asserted-by":"crossref","unstructured":"Han, X. et al. Fast and facile synthesis of amidine-incorporated degradable lipids for versatile mRNA delivery in vivo. Nat. Chem. 16, 1687\u20131697 (2024).","DOI":"10.1038\/s41557-024-01557-2"},{"key":"69017_CR4","doi-asserted-by":"publisher","first-page":"1364","DOI":"10.1038\/s41565-023-01453-9","volume":"18","author":"Y Zhang","year":"2023","unstructured":"Zhang, Y. et al. Close the cancer\u2013immunity cycle by integrating lipid nanoparticle\u2013mRNA formulations and dendritic cell therapy. Nat. Nanotechnol. 18, 1364\u20131374 (2023).","journal-title":"Nat. Nanotechnol."},{"key":"69017_CR5","doi-asserted-by":"crossref","unstructured":"Chatterjee, S., Kon, E., Sharma, P. & Peer, D. Endosomal escape: a bottleneck for LNP- mediated therapeutics. In Proc. National Academy of Sciences of the United States of America 121 (2024).","DOI":"10.1073\/pnas.2307800120"},{"key":"69017_CR6","doi-asserted-by":"crossref","unstructured":"Claudia P. A. et al. A multivalent nucleoside-modified mRNA vaccine against all known influenza virus subtype. Science 378, 899\u2013904 (2022).","DOI":"10.1126\/science.abm0271"},{"key":"69017_CR7","doi-asserted-by":"crossref","unstructured":"Creamer, A. et al. Modular synthesis of semiconducting graft copolymers to achieve \u201cclickable\u201d fluorescent nanoparticles with long circulation and specific cancer targeting. Adv. Mater. 36, 2300413 (2024).","DOI":"10.1002\/adma.202300413"},{"key":"69017_CR8","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1016\/j.cell.2020.07.024","volume":"182","author":"NN Zhang","year":"2020","unstructured":"Zhang, N. N. et al. A thermostable mRNA vaccine against COVID-19. Cell 182, 1271\u20131283 (2020).","journal-title":"Cell"},{"key":"69017_CR9","doi-asserted-by":"publisher","first-page":"1920","DOI":"10.1056\/NEJMoa2022483","volume":"383","author":"LA Jackson","year":"2020","unstructured":"Jackson, L. A. et al. An mRNA vaccine against SARS-CoV-2-preliminary report. N. Engl. J. Med. 383, 1920\u20131931 (2020).","journal-title":"N. Engl. J. Med."},{"key":"69017_CR10","first-page":"1970","volume":"384","author":"N Barda","year":"2021","unstructured":"Barda, N., Dagan, N. & Balicer, R. D. BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting REPLY. N. Engl. J. Med. 384, 1970\u20131970 (2021).","journal-title":"N. Engl. J. Med."},{"key":"69017_CR11","doi-asserted-by":"crossref","unstructured":"Fang, Z. et al. Omicron-specific mRNA vaccination alone and as a heterologous booster against SARS-CoV-2. Nat. Commun. 13, 3250 (2022).","DOI":"10.1038\/s41467-022-30878-4"},{"key":"69017_CR12","doi-asserted-by":"crossref","unstructured":"Jain, S., Venkataraman, A., Wechsler, M. E. & Peppas, N. A. Messenger RNA-based vaccines: past, present, and future directions in the context of the COVID-19 pandemic. Adv. Drug Deliv. Rev. 179, 114000 (2021).","DOI":"10.1016\/j.addr.2021.114000"},{"key":"69017_CR13","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-23997-x","volume":"12","author":"SLY Teo","year":"2021","unstructured":"Teo, S. L. Y. et al. Unravelling cytosolic delivery of cell penetrating peptides with a quantitative endosomal escape assay. Nat. Commun. 12, 3721 (2021).","journal-title":"Nat. Commun."},{"key":"69017_CR14","doi-asserted-by":"crossref","unstructured":"Liu, H. et al. Beyond the endosomal bottleneck: understanding the efficiency of mRNA\/LNP delivery. Adv. Funct. Mater. 34, 2404510 (2024).","DOI":"10.1002\/adfm.202404510"},{"key":"69017_CR15","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1038\/271672a0","volume":"271","author":"PR Cullis","year":"1978","unstructured":"Cullis, P. R. & Hope, M. J. Effects of fusogenic agent on membrane structure of erythrocyte-ghosts and mechanism of membrane-fusion. Nature 271, 672\u2013674 (1978).","journal-title":"Nature"},{"key":"69017_CR16","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1038\/nbt.1602","volume":"28","author":"SC Semple","year":"2010","unstructured":"Semple, S. C. et al. Rational design of cationic lipids for siRNA delivery. Nat. Biotechnol. 28, 172\u2013U118 (2010).","journal-title":"Nat. Biotechnol."},{"key":"69017_CR17","doi-asserted-by":"crossref","unstructured":"Yu, H. et al. Real-time pH-dependent self-assembly of ionisable lipids from COVID-19 vaccines and in situ nucleic acid complexation. Angew. Chem., Int. Ed. 62, e202304977 (2023).","DOI":"10.1002\/anie.202304977"},{"key":"69017_CR18","doi-asserted-by":"publisher","first-page":"7825","DOI":"10.1021\/acsnano.3c04507","volume":"18","author":"H Zhang","year":"2024","unstructured":"Zhang, H. et al. Fluorinated lipid nanoparticles for enhancing mRNA delivery efficiency. ACS Nano 18, 7825\u20137836 (2024).","journal-title":"ACS Nano"},{"key":"69017_CR19","doi-asserted-by":"publisher","first-page":"35835","DOI":"10.1021\/acsami.0c08268","volume":"12","author":"X Ke","year":"2020","unstructured":"Ke, X. et al. Surface-functionalized PEGylated nanoparticles deliver messenger RNA to pulmonary immune cells. Acs Appl. Mater. Interfaces 12, 35835\u201335844 (2020).","journal-title":"Acs Appl. Mater. Interfaces"},{"key":"69017_CR20","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1038\/s41563-024-01934-9","volume":"23","author":"R van der Meel","year":"2024","unstructured":"van der Meel, R., Grisoni, F. & Mulder, W. J. M. Lipid discovery for mRNA delivery guided by machine learning. Nat. Mater. 23, 880\u2013881 (2024).","journal-title":"Nat. Mater."},{"key":"69017_CR21","doi-asserted-by":"crossref","unstructured":"Zhao, S. et al. Acid-degradable lipid nanoparticles enhance the delivery of mRNA. Nat. Nanotechnol. 19, 1702\u20131711 (2024).","DOI":"10.1038\/s41565-024-01765-4"},{"key":"69017_CR22","first-page":"24765","volume":"145","author":"H Yu","year":"2023","unstructured":"Yu, H. et al. Inverse cubic and hexagonal mesophase evolution within ionizable lipid nanoparticles correlates with mRNA transfection in macrophages. J. Am. Chem. Soc. 145, 24765\u201324774 (2023).","journal-title":"J. Am. Chem. Soc."},{"key":"69017_CR23","doi-asserted-by":"publisher","first-page":"18440","DOI":"10.1021\/jp303267y","volume":"116","author":"AKK Leung","year":"2012","unstructured":"Leung, A. K. K. et al. Lipid nanoparticles containing siRNA synthesized by microfluidic mixing exhibit an electron-dense nanostructured core.  J. Phys. Chem. C. 116, 18440\u201318450 (2012).","journal-title":"J. Phys. Chem. C."},{"key":"69017_CR24","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1038\/s41565-023-01548-3","volume":"19","author":"AY Jiang","year":"2023","unstructured":"Jiang, A. Y. et al. Combinatorial development of nebulized mRNA delivery formulations for the lungs. Nat. Nanotechnol. 19, 364\u2013375 (2023).","journal-title":"Nat. Nanotechnol."},{"key":"69017_CR25","doi-asserted-by":"publisher","first-page":"e2310491120","DOI":"10.1073\/pnas.2310491120","volume":"120","author":"J Philipp","year":"2023","unstructured":"Philipp, J. et al. pH-dependent structural transitions in cationic ionizable lipid mesophases are critical for lipid nanoparticle function. Proc. Natl. Acad. Sci. USA 120, e2310491120\u2013e2310491120 (2023).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"69017_CR26","doi-asserted-by":"crossref","unstructured":"Goldbach, N. et al. De novo design of monomeric helical bundles for pH-controlled membrane lysis. Protein Sci. 32, e4769 (2023).","DOI":"10.2210\/pdb8gl3\/pdb"},{"key":"69017_CR27","doi-asserted-by":"crossref","unstructured":"Haspot, F. et al. Human cytomegalovirus entry into dendritic cells occurs via a macropinocytosis-like pathway in a pH-independent and cholesterol-dependent manner. PLoS ONE 7, e34795 (2012).","DOI":"10.1371\/journal.pone.0034795"},{"key":"69017_CR28","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1038\/s41565-021-00858-8","volume":"16","author":"JJ Rennick","year":"2021","unstructured":"Rennick, J. J., Johnston, A. P. R. & Parton, R. G. Key principles and methods for studying the endocytosis of biological and nanoparticle therapeutics. Nat. Nanotechnol. 16, 266\u2013276 (2021).","journal-title":"Nat. Nanotechnol."},{"key":"69017_CR29","doi-asserted-by":"crossref","unstructured":"Wandinger-Ness, A. & Zerial, M. Rab proteins and the compartmentalization of the endosomal system. Cold Spring Harbor Perspect. Biol. 6, a022616 (2014).","DOI":"10.1101\/cshperspect.a022616"},{"key":"69017_CR30","doi-asserted-by":"crossref","unstructured":"Klumperman, J. & Raposo, G. The complex ultrastructure of the endolysosomal system. Cold Spring Harbor Perspect. Biol. 6, a016857 (2014).","DOI":"10.1101\/cshperspect.a016857"},{"key":"69017_CR31","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1038\/nbt.2614","volume":"31","author":"G Sahay","year":"2013","unstructured":"Sahay, G. et al. Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling. Nat. Biotechnol. 31, 653\u2013U119 (2013).","journal-title":"Nat. Biotechnol."},{"key":"69017_CR32","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1038\/35052055","volume":"2","author":"M Zerial","year":"2001","unstructured":"Zerial, M. & McBride, H. Rab proteins as membrane organizers. Nat. Rev. Mol. Cell Biol. 2, 107\u2013117 (2001).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"69017_CR33","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1038\/nrm2745","volume":"10","author":"P Saftig","year":"2009","unstructured":"Saftig, P. & Klumperman, J. Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nat. Rev. Mol. Cell Biol. 10, 623\u2013635 (2009).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"69017_CR34","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1038\/s41565-020-0669-6","volume":"15","author":"Q Cheng","year":"2020","unstructured":"Cheng, Q. et al. Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR\u2013Cas gene editing. Nat. Nanotechnol. 15, 313\u2013320 (2020).","journal-title":"Nat. Nanotechnol."},{"key":"69017_CR35","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-42948-2","volume":"14","author":"T Wei","year":"2023","unstructured":"Wei, T. et al. Lung SORT LNPs enable precise homology-directed repair mediated CRISPR\/Cas genome correction in cystic fibrosis models. Nat. Commun. 14, 7322 (2023).","journal-title":"Nat. Commun."},{"key":"69017_CR36","doi-asserted-by":"publisher","first-page":"1311","DOI":"10.7150\/thno.79326","volume":"13","author":"X Hong","year":"2023","unstructured":"Hong, X. et al. WT1+glomerular parietal epithelial progenitors promote renal proximal tubule regeneration after severe acute kidney injury. Theranostics 13, 1311\u20131324 (2023).","journal-title":"Theranostics"},{"key":"69017_CR37","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-43730-0","volume":"14","author":"AJ Murphy","year":"2023","unstructured":"Murphy, A. J. et al. Genetic and epigenetic features of bilateral Wilms tumor predisposition in patients from the Children\u2019s Oncology Group AREN18B5-Q. Nat. Commun. 14, 8006 (2023).","journal-title":"Nat. Commun."},{"key":"69017_CR38","doi-asserted-by":"publisher","first-page":"1842","DOI":"10.1038\/s41375-023-01980-3","volume":"37","author":"Y Fl\u00f8isand","year":"2023","unstructured":"Fl\u00f8isand, Y. et al. WT1 and PRAME RNA-loaded dendritic cell vaccine as maintenance therapy in de novo AML after intensive induction chemotherapy. Leukemia 37, 1842\u20131849 (2023).","journal-title":"Leukemia"},{"key":"69017_CR39","doi-asserted-by":"publisher","first-page":"3306","DOI":"10.3390\/jcm11123306","volume":"11","author":"D Lazzarotto","year":"2022","unstructured":"Lazzarotto, D. & Candoni, A. The role of wilms\u2019 tumor gene (WT1) expression as a marker of minimal residual disease in acute myeloid leukemia. J. Clin. Med. 11, 3306 (2022).","journal-title":"J. Clin. Med."},{"key":"69017_CR40","doi-asserted-by":"publisher","first-page":"F3","DOI":"10.1152\/ajprenal.00248.2023","volume":"326","author":"E Torban","year":"2024","unstructured":"Torban, E. & Goodyer, P. Wilms\u2019 tumor gene 1: lessons from the interface between kidney development and cancer. Am. J. Physiol. Ren. Physiol. 326, F3\u2013F19 (2024).","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"69017_CR41","doi-asserted-by":"publisher","first-page":"e2308556","DOI":"10.1002\/advs.202308556","volume":"11","author":"G Wang","year":"2024","unstructured":"Wang, G. et al. Kidney organoid modeling of WT1 mutations reveals key regulatory paths underlying podocyte development. Adv. Sci. 11, e2308556 (2024).","journal-title":"Adv. Sci."},{"key":"69017_CR42","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1007\/978-1-0716-2954-3_22","volume":"2622","author":"AS Ubhe","year":"2023","unstructured":"Ubhe, A. S. Imaging of liposomes by negative staining transmission electron microscopy and cryogenic transmission electron microscopy. Methods Mol. Biol. 2622, 245\u2013251 (2023).","journal-title":"Methods Mol. Biol."},{"key":"69017_CR43","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/j.ijpharm.2010.10.025","volume":"403","author":"R Crawford","year":"2011","unstructured":"Crawford, R. et al. Analysis of lipid nanoparticles by Cryo-EM for characterizing siRNA delivery vehicles. Int. J. Pharmaceutics 403, 237\u2013244 (2011).","journal-title":"Int. J. Pharmaceutics"},{"key":"69017_CR44","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1007\/s00396-020-04657-w","volume":"298","author":"Z Kochovski","year":"2020","unstructured":"Kochovski, Z., Chen, G., Yuan, J. & Lu, Y. Cryo-Electron microscopy for the study of self-assembled poly(ionic liquid) nanoparticles and protein supramolecular structures. Colloid Polym. Sci. 298, 707\u2013717 (2020).","journal-title":"Colloid Polym. Sci."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-69017-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-69017-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-69017-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T01:01:56Z","timestamp":1772672516000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-69017-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,30]]},"references-count":44,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["69017"],"URL":"https:\/\/doi.org\/10.1038\/s41467-026-69017-8","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,30]]},"assertion":[{"value":"14 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 January 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 January 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"We have updated the Competing Interests statement to disclose a pending patent application. Specifically, we state that YC and TL are inventors on a patent application NMKX-25001 related to the technology described in this manuscript.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2187"}}