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Lipid nanoparticles are widely used as delivery platforms, yet how their internal organization can be engineered to coordinate multiple innate immune signals remains poorly understood. Here, we designed a hybrid lipid nanoparticle adjuvant that coformulates two clinically relevant immune stimulators targeting toll-like receptor 4 (TLR4) and TLR9. By blending two ionizable lipids, the nanoparticles self-assemble into a layered structure with a raft-associated ordered outer shell and an inner core, with apparent enrichment of monophosphoryl lipid A (MPLA) toward the particle surface and CpG toward the interior, as suggested by our experimental and simulation analyses. This organization is consistent with a relay-like activation pattern that may contribute to strong immune responses while potentially reducing early inflammatory reactions. The hybrid adjuvant enhances antibody quality, cellular immunity, and protective efficacy under the tested conditions, across multiple vaccine antigens and animal models, with performance comparable to or exceeding benchmark adjuvants. These findings suggest that controlling nanoscale lipid organization provides a useful strategy for improving vaccine adjuvant performance.<\/jats:p>","DOI":"10.1021\/acsnano.6c09358","type":"journal-article","created":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T09:46:18Z","timestamp":1787478378000},"page":"24004-24019","source":"Crossref","is-referenced-by-count":0,"title":["Layered\nLipid Nanoparticle Adjuvants Coordinate Toll-Like\nReceptor 4 and Toll-Like Receptor 9 Activation with Enhanced Immunity\nand Improved Tolerability"],"prefix":"10.1021","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3055-6042","authenticated-orcid":true,"given":"Haolin","family":"Chen","sequence":"first","affiliation":[{"name":"Sun Yat-sen University , , ,","place":["Guangzhou, China, 510006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9764-8027","authenticated-orcid":true,"given":"Ruifeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Henan University , , ,","place":["Kaifeng, China, 475004"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University , , ,","place":["Guangzhou, China, 510006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyu","family":"Yang","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University , , ,","place":["Guangzhou, China, 510006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenfu","family":"Wen","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University , , ,","place":["Guangzhou, China, 510006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyan","family":"Li","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University , , ,","place":["Guangzhou, China, 510006"]},{"name":"Henan University , , ,","place":["Zhengzhou, China, 450046"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8438-6961","authenticated-orcid":true,"given":"Zhijia","family":"Liu","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University , , ,","place":["Guangzhou, China, 510006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dang","family":"Fan","sequence":"additional","affiliation":[{"name":"Henan University , , ,","place":["Kaifeng, China, 475004"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhua","family":"Xu","sequence":"additional","affiliation":[{"name":"Henan University , , ,","place":["Kaifeng, China, 475004"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Li","sequence":"additional","affiliation":[{"name":"Henan University , , ,","place":["Kaifeng, China, 475004"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0350-7475","authenticated-orcid":true,"given":"Hong","family":"Liu","sequence":"additional","affiliation":[{"name":"Henan University , , ,","place":["Zhengzhou, China, 450046"]},{"name":"Henan University , , ,","place":["Kaifeng, China, 475000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6133-4977","authenticated-orcid":true,"given":"Lixin","family":"Liu","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University , , ,","place":["Guangzhou, China, 510006"]},{"name":"The People\u2019s Hospital of Guangxi Zhuang Autonomous Region , , ,","place":["Nanning, China, 530021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2843-5543","authenticated-orcid":true,"given":"Yongming","family":"Chen","sequence":"additional","affiliation":[{"name":"Sun Yat-sen University , , ,","place":["Guangzhou, China, 510006"]},{"name":"Henan University , , ,","place":["Kaifeng, China, 475004"]},{"name":"Henan University , , ,","place":["Zhengzhou, China, 450046"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"2026090307000159700_cit1","doi-asserted-by":"publisher","first-page":"298","DOI":"10.3389\/fmicb.2020.00298","article-title":"Subunit Vaccines Against\nEmerging Pathogenic Human Coronaviruses","volume":"11","author":"Wang","year":"2020","journal-title":"Front.\nMicrobiol."},{"issue":"12","key":"2026090307000159700_cit2","doi-asserted-by":"publisher","first-page":"1597","DOI":"10.1038\/nm.3409","article-title":"Key Roles of Adjuvants\nin Modern\nVaccines","volume":"19","author":"Reed","year":"2013","journal-title":"Nat. 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Immunol."},{"issue":"29","key":"2026090307000159700_cit6","doi-asserted-by":"publisher","first-page":"4341","DOI":"10.1016\/j.vaccine.2011.09.061","article-title":"The Mechanism of Action\nof MF59 \u2013 An Innately Attractive Adjuvant Formulation","volume":"30","author":"O\u2019Hagan","year":"2012","journal-title":"Vaccine"},{"issue":"1","key":"2026090307000159700_cit7","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1080\/14760584.2016.1213632","article-title":"Adjuvant System\nAS01: Helping to Overcome the Challenges\nof Modern Vaccines","volume":"16","author":"Didierlaurent","year":"2017","journal-title":"Expert Rev. Vaccines"},{"issue":"6","key":"2026090307000159700_cit8","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1038\/s41573-021-00163-y","article-title":"Emerging Concepts in the Science\nof Vaccine Adjuvants","volume":"20","author":"Pulendran","year":"2021","journal-title":"Nat. Rev. Drug Discovery"},{"key":"2026090307000159700_cit9","doi-asserted-by":"publisher","first-page":"152905","DOI":"10.1016\/j.phymed.2019.152905","article-title":"Updated\nInsights into the Mechanism of Action and Clinical Profile of the\nImmunoadjuvant QS-21: A Review","volume":"60","author":"Lacaille-Dubois","year":"2019","journal-title":"Phytomedicine"},{"key":"2026090307000159700_cit10","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.714","article-title":"Interaction of Innate Immune and\nAdaptive Immune System","volume":"5","author":"Wang","year":"2020","journal-title":"MedComm."},{"key":"2026090307000159700_cit11","doi-asserted-by":"publisher","first-page":"1043109","DOI":"10.3389\/fimmu.2023.1043109","article-title":"New-Age Vaccine Adjuvants, Their\nDevelopment, and Future Perspective","volume":"14","author":"Verma","year":"2023","journal-title":"Front.\nImmunol."},{"issue":"7","key":"2026090307000159700_cit12","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.3390\/vaccines10071120","article-title":"Advances\nin Infectious Disease Vaccine Adjuvants","volume":"10","author":"Fan","year":"2022","journal-title":"Vaccines"},{"key":"2026090307000159700_cit13","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1016\/j.actbio.2022.12.042","article-title":"Carrier-Free Subunit\nNanovaccine Amplifies Immune Responses\nagainst Tumors and Viral Infections","volume":"158","author":"Chen","year":"2023","journal-title":"Acta Biomater."},{"issue":"1","key":"2026090307000159700_cit14","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1002\/JLB.3MIR1218-483RR","article-title":"Below the\nSurface: The Inner Lives of TLR4 and TLR9","volume":"106","author":"Marongiu","year":"2019","journal-title":"J.\nLeukoc. Biol."},{"issue":"5","key":"2026090307000159700_cit15","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1021\/acs.accounts.9b00631","article-title":"Small-Molecule\nModulators\nof Toll-like Receptors","volume":"53","author":"Wang","year":"2020","journal-title":"Acc. Chem. Res."},{"key":"2026090307000159700_cit16","doi-asserted-by":"publisher","first-page":"812774","DOI":"10.3389\/fimmu.2022.812774","article-title":"Toll-Like Receptor\nSignaling and Its Role in Cell-Mediated Immunity","volume":"13","author":"Duan","year":"2022","journal-title":"Front. Immunol."},{"key":"2026090307000159700_cit17","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.jconrel.2018.04.041","article-title":"Dual TLR Agonist Nanodiscs as a Strong\nAdjuvant System for Vaccines and Immunotherapy","volume":"282","author":"Kuai","year":"2018","journal-title":"J. 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Immunol."},{"key":"2026090307000159700_cit20","doi-asserted-by":"publisher","first-page":"1561297","DOI":"10.3389\/fimmu.2025.1561297","article-title":"Evaluation of Dual Pathogen Recognition\nReceptor Agonists\nas Adjuvants for Respiratory Syncytial Virus - Virus-like Particles\nfor Pulmonary Delivery","volume":"16","author":"Mandviwala","year":"2025","journal-title":"Front. Immunol."},{"key":"2026090307000159700_cit21","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.antiviral.2016.06.002","article-title":"Signaling\nvia Pattern Recognition\nReceptors NOD2 and TLR2 Contributes to Immunomodulatory Control of\nLethal Pneumovirus Infection","volume":"132","author":"Rice","year":"2016","journal-title":"Antiviral Res."},{"issue":"7","key":"2026090307000159700_cit22","doi-asserted-by":"publisher","first-page":"6328","DOI":"10.1007\/s12274-022-4282-x","article-title":"STING and TLR7\/8\nAgonists-Based Nanovaccines for Synergistic Antitumor Immune Activation","volume":"15","author":"Zhang","year":"2022","journal-title":"Nano Res."},{"issue":"24","key":"2026090307000159700_cit23","doi-asserted-by":"publisher","first-page":"6091","DOI":"10.3390\/cancers14246091","article-title":"Combination\nof STING and TLR 7\/8 Agonists as Vaccine Adjuvants for Cancer Immunotherapy","volume":"14","author":"Bhatnagar","year":"2022","journal-title":"Cancers"},{"issue":"3","key":"2026090307000159700_cit24","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1038\/s41578-021-00372-2","article-title":"Designing Spatial and Temporal Control of Vaccine Responses","volume":"7","author":"Roth","year":"2022","journal-title":"Nat. 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Mater."},{"issue":"6","key":"2026090307000159700_cit25","doi-asserted-by":"publisher","first-page":"1168","DOI":"10.1016\/j.cell.2012.11.011","article-title":"Signaling\nOrganelles of the Innate Immune System","volume":"151","author":"Kagan","year":"2012","journal-title":"Cell"},{"issue":"6","key":"2026090307000159700_cit26","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1016\/j.cell.2020.02.041","article-title":"Toll-like Receptors\nand the Control of Immunity","volume":"180","author":"Fitzgerald","year":"2020","journal-title":"Cell"},{"issue":"1","key":"2026090307000159700_cit27","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1111\/imm.12617","article-title":"Lipid Rafts\nin Immune Signalling:\nCurrent Progress and Future Perspective","volume":"149","author":"Varshney","year":"2016","journal-title":"Immunology"},{"issue":"3","key":"2026090307000159700_cit28","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1007\/s00018-014-1762-5","article-title":"Co-Operation\nof TLR4 and Raft Proteins in LPS-Induced pro-Inflammatory Signaling","volume":"72","author":"P\u0142o\u0301ciennikowska","year":"2015","journal-title":"Cell. Mol. Life Sci."},{"issue":"7222","key":"2026090307000159700_cit29","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1038\/nature07405","article-title":"The Ectodomain of\nToll-like Receptor 9 Is Cleaved to Generate a Functional Receptor","volume":"456","author":"Ewald","year":"2008","journal-title":"Nature"},{"key":"2026090307000159700_cit30","doi-asserted-by":"publisher","DOI":"10.7554\/elife.00291","article-title":"UNC93B1Mediates Differential Trafficking\nof Endosomal TLRs","volume":"2","author":"Lee","year":"2013","journal-title":"eLife"},{"issue":"32","key":"2026090307000159700_cit31","doi-asserted-by":"publisher","first-page":"2402688","DOI":"10.1002\/adhm.202402688","article-title":"PEI-Engineered Lipid@PLGA Hybrid Nanoparticles for\nMultimodal Delivery of Antigens and Immune Adjuvants to the Respiratory\nMucosa","volume":"13","author":"Brusco","year":"2024","journal-title":"Adv. Healthc. Mater."},{"key":"2026090307000159700_cit32","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.biomaterials.2016.03.039","article-title":"Artificial Bacterial Biomimetic Nanoparticles\nSynergize Pathogen-Associated Molecular Patterns for Vaccine Efficacy","volume":"97","author":"Siefert","year":"2016","journal-title":"Biomaterials"},{"key":"2026090307000159700_cit33","doi-asserted-by":"publisher","first-page":"148058","DOI":"10.1016\/j.ijbiomac.2025.148058","article-title":"Incorporation of\nMonophosphoryl Lipid A and CpG-Oligodeoxynucleotides into Lipid Nanoparticles\nActivates Toll-like Receptor Signaling Pathways While Maintaining\nAntigen Expression for mRNA-Based Vaccinations","volume":"330","author":"Vaquero","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"issue":"11","key":"2026090307000159700_cit34","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1038\/nri2868","article-title":"Vaccine Delivery:\nA Matter of Size, Geometry, Kinetics\nand Molecular Patterns","volume":"10","author":"Bachmann","year":"2010","journal-title":"Nat. Rev. Immunol."},{"issue":"1","key":"2026090307000159700_cit35","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1177\/1753425919852695","article-title":"Lipids That Directly\nRegulate Innate Immune Signal\nTransduction","volume":"26","author":"Barnett","year":"2020","journal-title":"Innate Immun."},{"issue":"2","key":"2026090307000159700_cit36","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/s41573-020-0090-8","article-title":"Engineering Precision Nanoparticles\nfor Drug Delivery","volume":"20","author":"Mitchell","year":"2021","journal-title":"Nat. Rev. Drug Discovery"},{"issue":"8","key":"2026090307000159700_cit37","doi-asserted-by":"publisher","first-page":"2792","DOI":"10.1021\/jacsau.4c00568","article-title":"Precision\nNanovaccines for Potent\nVaccination","volume":"4","author":"Liu","year":"2024","journal-title":"JACS Au"},{"key":"2026090307000159700_cit38","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/j.jconrel.2019.10.025","article-title":"Co-Encapsulation of\nSynthetic Lipidated\nTLR4 and TLR7\/8 Agonists in the Liposomal Bilayer Results in a Rapid,\nSynergistic Enhancement of Vaccine-Mediated Humoral Immunity","volume":"315","author":"Short","year":"2019","journal-title":"J. Controlled Release"},{"issue":"7335","key":"2026090307000159700_cit39","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1038\/nature09737","article-title":"Programming the Magnitude and Persistence\nof Antibody Responses with Innate Immunity","volume":"470","author":"Kasturi","year":"2011","journal-title":"Nature"},{"issue":"8","key":"2026090307000159700_cit40","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1038\/ni1223","article-title":"Selected Toll-like\nReceptor Agonist Combinations Synergistically Trigger a T Helper Type\n1\u2013Polarizing Program in Dendritic Cells","volume":"6","author":"Napolitani","year":"2005","journal-title":"Nat. Immunol."},{"issue":"1","key":"2026090307000159700_cit41","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/s44386-025-00014-5","article-title":"Understanding\nthe Molecular Insights of Marketed Liposomal Drugs Using Molecular\nDynamics Simulations of Reduced Scale Coarse-Grained Models","volume":"2","author":"Wang","year":"2025","journal-title":"Npj Drug Discov"},{"key":"2026090307000159700_cit42","doi-asserted-by":"publisher","first-page":"125114","DOI":"10.1016\/j.ijpharm.2024.125114","article-title":"Understanding the Self-Assembly\nand Molecular Structure of mRNA Lipid Nanoparticles at Real Size:\nInsights from the Ultra-Large-Scale Simulation","volume":"670","author":"Wang","year":"2025","journal-title":"Int. J. Pharm."},{"key":"2026090307000159700_cit43","doi-asserted-by":"publisher","first-page":"125571","DOI":"10.1016\/j.ijpharm.2025.125571","article-title":"Regulating\nmRNA Endosomal Escape through Lipid Rafts:\nA Review","volume":"675","author":"Wang","year":"2025","journal-title":"Int. J. Pharm."},{"issue":"6","key":"2026090307000159700_cit44","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1038\/nprot.2012.059","article-title":"Elucidating Membrane Structure and Protein Behavior\nUsing Giant Plasma Membrane Vesicles","volume":"7","author":"Sezgin","year":"2012","journal-title":"Nat. Protoc."},{"issue":"2","key":"2026090307000159700_cit45","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1007\/s00232-022-00233-1","article-title":"Mechanism\nof Membrane Fusion: Interplay\nof Lipid and Peptide","volume":"255","author":"Joardar","year":"2022","journal-title":"J. Membr. Biol."},{"issue":"7","key":"2026090307000159700_cit46","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1038\/nbt.2612","article-title":"Image-Based Analysis\nof Lipid Nanoparticle\u2013Mediated siRNA Delivery, Intracellular\nTrafficking and Endosomal Escape","volume":"31","author":"Gilleron","year":"2013","journal-title":"Nat. Biotechnol."},{"issue":"17","key":"2026090307000159700_cit47","doi-asserted-by":"publisher","first-page":"4116","DOI":"10.3390\/ijms20174116","article-title":"3dRNA v2.0: An Updated\nWeb Server for RNA 3D Structure Prediction","volume":"20","author":"Wang","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"2026090307000159700_cit48","doi-asserted-by":"publisher","first-page":"4849","DOI":"10.1016\/j.csbj.2023.09.024","article-title":"CHAPERONg: A Tool\nfor Automated GROMACS-Based Molecular Dynamics\nSimulations and Trajectory Analyses","volume":"21","author":"Yekeen","year":"2023","journal-title":"Comput.\nStruct. Biotechnol. J."},{"key":"2026090307000159700_cit49","doi-asserted-by":"publisher","first-page":"120116","DOI":"10.1016\/j.molliq.2022.120116","article-title":"Effects of\nThermostats\/Barostats on Physical Properties of Liquids by Molecular\nDynamics Simulations","volume":"365","author":"Ke","year":"2022","journal-title":"J. Mol. Liq."},{"issue":"1","key":"2026090307000159700_cit50","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual Molecular\nDynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph."},{"issue":"10","key":"2026090307000159700_cit51","doi-asserted-by":"publisher","first-page":"6281","DOI":"10.1021\/acs.jctc.1c00645","article-title":"gmx_MMPBSA:\nA New Tool to Perform End-State Free Energy Calculations with GROMACS","volume":"17","author":"Valde\u0301s-Tresanco","year":"2021","journal-title":"J. Chem. 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