ArticlePublished: 01 July 2026Xiaoyu Gao1,2,Liting Chen1,Qingqing Feng1,Wei Lv1,Peijun Xu1,Zetao Yu1,Xinwei Wang1,Qinyi Zhang1,2,Tianyu Shao1,Yichao Lu1,Wenna Li1,Jiabeini Zhang1,Dingfei Qian1,Xinze Du1,Jiajia Zou3,Linjie Chen3,Guangjun Nie ORCID: orcid.org/0000-0001-5040-97931,2,Keman Cheng ORCID: orcid.org/0009-0006-6646-00951,2 &…Xiao Zhao ORCID: orcid.org/0000-0002-4504-56701,2 Nature Materials (2026) Cite this articleSave articleView saved researchSubjectsBiomaterials – vaccinesDrug deliveryProtein vaccinesAbstractAlthough injectable respiratory syncytial virus (RSV) pre-F vaccines are clinically established, effective intranasal alternatives remain elusive. Geometric and surface antigen display properties are critical for respiratory B cell activation, yet lack strategies for systematic optimization. Here we report a library of DNA nanocarriers with controlled dimensions and sizes, aiming to systemically evaluate the influence of geometric properties on intranasal retention. Taking advantage of the precise control on DNA nanocarriers and antigen functionalization, we organized the surface antigen patterns of pre-F monomers on DNA nanocarriers to maximize B cell activation. The optimized DNA nanocarrier-based vaccine elicited humoral immunity in mice comparable to that induced by the clinically approved trimeric mRNA vaccine against RSV, but with greater durability. While intramuscular mRNA vaccines failed to induce effective respiratory mucosal immunity, the intranasal DNA nanocarrier-based vaccine achieved robust local and systemic immune activation, conferring potent protection against RSV infection. This rational design of intranasal RSV vaccines may be a general strategy for testing and advancing potent intranasal vaccines for a range of infectious respiratory diseases.This is a preview of subscription content, access via your institutionAccess optionsAccess Nature and 54 other Nature Portfolio journalsGet Nature+, our best-value online-access subscription27,99 € / 30 dayscancel any timeLearn moreSubscribe to this journalReceive 12 print issues and online access269,00 € per yearonly 22,42 € per issueLearn moreBuy this articlePurchase on SpringerLinkInstant access to the full article PDF.39,95 €Prices may be subject to local taxes which are calculated during checkoutFig. 1: Biodistribution of DNA nanocarriers with different geometric properties after intranasal administration.Fig. 2: Construction of the DNA nanocarrier-based vaccine displaying multiple RSV pre-F monomers.Fig. 3: Structure–function relationship between surface antigen patterns and B cell activation capacity of ICO-RSV vaccines.Fig. 4: Biodistribution of ICO-RSV vaccines after intranasal administration.Fig. 5: Tracking of antigen presentation and germinal centre responses after intranasal ICO-RSV vaccination in mice.Fig. 6: Immunologic monitoring after intranasal ICO-RSV vaccination in mice.Data availabilityThe data supporting the results of this study are available within the Article and its Supplementary Information. There are no data from third-party or publicly available datasets. For any inquiries regarding the source data, please contact the corresponding authors. Source data are provided with this paper.ReferencesShi, T. et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet 390, 946–958 (2017).Article PubMed PubMed Central Google Scholar Kim, H. W. et al. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am. J. Epidemiol. 89, 422–434 (1969).Article CAS PubMed Google Scholar Kapikian, A. Z., Mitchell, R. H., Chanock, R. M., Shvedoff, R. A. & Stewart, C. E. An epidemiologic study of altered clinical reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated with an inactivated RS virus vaccine. Am. J. 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Yang from Renji Hospital, School of Medicine, Shanghai Jiao Tong University for his help with the design of DNA nanocarriers.FundingX.Z. discloses support for the research of this work from the Beijing Municipal Science and Technology Commission (grant no. Z231100007223011), the National Natural Science Foundation of China (grant nos. 32222045 and 32171384), the CAS Project for Young Scientists in Basic Research (grant no. YSBR-010), and the National Key R&D Program of China (grant nos. 2022YFB3808100 and 2021YFA0909900). K.C. discloses support for the research of this work from the National Natural Science Foundation of China (grant nos. 32471450 and 82402462).Author informationAuthors and AffiliationsBeijing Key Laboratory of Nanocarriers for Drug Delivery, National Center for Nanoscience and Technology of China, Beijing, ChinaXiaoyu Gao, Liting Chen, Qingqing Feng, Wei Lv, Peijun Xu, Zetao Yu, Xinwei Wang, Qinyi Zhang, Tianyu Shao, Yichao Lu, Wenna Li, Jiabeini Zhang, Dingfei Qian, Xinze Du, Guangjun Nie, Keman Cheng & Xiao ZhaoUniversity of Chinese Academy of Sciences, Beijing, ChinaXiaoyu Gao, Qinyi Zhang, Guangjun Nie, Keman Cheng & Xiao ZhaoBeijing Intell Nanomedicine, Beijing, ChinaJiajia Zou & Linjie ChenAuthorsXiaoyu GaoView author publicationsSearch author on:PubMed Google ScholarLiting ChenView author publicationsSearch author on:PubMed Google ScholarQingqing FengView author publicationsSearch author on:PubMed Google ScholarWei LvView author publicationsSearch author on:PubMed Google ScholarPeijun XuView author publicationsSearch author on:PubMed Google ScholarZetao YuView author publicationsSearch author on:PubMed Google ScholarXinwei WangView author publicationsSearch author on:PubMed Google ScholarQinyi ZhangView author publicationsSearch author on:PubMed Google ScholarTianyu ShaoView author publicationsSearch author on:PubMed Google ScholarYichao LuView author publicationsSearch author on:PubMed Google ScholarWenna LiView author publicationsSearch author on:PubMed Google ScholarJiabeini ZhangView author publicationsSearch author on:PubMed Google ScholarDingfei QianView author publicationsSearch author on:PubMed Google ScholarXinze DuView author publicationsSearch author on:PubMed Google ScholarJiajia ZouView author publicationsSearch author on:PubMed Google ScholarLinjie ChenView author publicationsSearch author on:PubMed Google ScholarGuangjun NieView author publicationsSearch author on:PubMed Google ScholarKeman ChengView author publicationsSearch author on:PubMed Google ScholarXiao ZhaoView author publicationsSearch author on:PubMed Google ScholarContributionsX.G., K.C. and X.Z. designed the research. X.G., Liting Chen, Q.F., W.Lv, P.X., Z.Y., X.W., Q.Z., T.S., Y.L., W.Li, J.Z., D.Q. and X.D. performed the experiments. J.Z., Linjie Chen and G.N. participated in the program discussion. X.G., G.N., K.C. and X.Z. wrote the paper. X.Z. conceived and supervised the project.Corresponding authorsCorrespondence to Guangjun Nie, Keman Cheng or Xiao Zhao.Ethics declarationsCompeting interestsQ.F., J.Z. and X.Z. are inventors on a filed provisional application of Chinese patent (Nano-assembly of antigens based on DNA origami and the application in vaccine) submitted by the National Center for Nanoscience and Technology and Beijing Intell Nanomedicine that covers the potential diagnostic and therapeutic uses of DNA–antigen complexes. X.Z., G.N., X.G. and K.C. are inventors on a filed provisional application of Chinese patent (A subunit vaccine based on DNA origami and the application in vaccine) submitted by the National Center for Nanoscience that covers the potential therapeutic uses of ICO-RSV. The other authors declare no competing interests.Peer reviewPeer review informationNature Materials thanks Xing Wang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended dataExtended Data Fig. 1 Evaluation of immune protection by intranasal ICO-RSV vaccination against RSV challenges in mice.(a) Schematic of immunization and challenge protocol. Mice were immunized on days 0 and 14 with the indicated formulations via intranasal delivery, including TAE-Mg2+ buffer (Control), ICO-RSV-UNI, and ICO-RSV. On day 28, the mice were challenged with RSV (Long strain) via intranasal inoculation. BALF and NALF were collected on days 31 and 42 for antibody titer analysis, while lung tissues were used for viral load measurement and immune cell infiltration evaluation. (b) RSV viral load in lung tissue on days 31 and 42, measured by reverse transcription quantitative polymerase chain reaction (RT-qPCR; n = 6 mice). (c, d) Histopathological analysis of lung tissue on days 31 (c) and 42 (d), stained with hematoxylin and eosin (H&E). Scale bar (black), 100 μm. The experiments (c, d) were independently repeated three times with similar results. (e, f) Immunohistochemical analysis of RSV nucleocapsid protein in lung tissue on days 31 (e) and 42 (f). Scale bar (black), 20 μm. The experiments (e, f) were independently repeated three times with similar results. (g, h) Immunofluorescence analysis of CD8 + T cells in lung tissue on days 31 (g) and 42 (h). Red indicates CD8 + T cells, and blue represents cell nuclei. Scale bar (gray), 1000 µm. Scale bar (white), 50 µm. The experiments (g, h) were independently repeated three times with similar results. (i) Schematic of the evaluation of immune responses, including the measurement of binding and neutralizing antibodies in the serum, NALF, and BALF collected on day 28. (j–l) IgG titer from RSV Pre-F trimers on day 28 in serum (j), NALF (k), and BALF (l; n = 6 mice). (m, n) IgA titer from RSV Pre-F trimers on day 28 in NALF (m) and BALF (n; n = 6 mice). (o–q) Neutralizing antibody titers (MN50) on day 28 in serum (o), NALF (p), and BALF (q), as measured by microneutralization assays (n = 6 mice). The data were processed on GraphPad Prism 8 and are presented as the mean ± SD (b) and mean ± SEM (j–q). The dashed lines in panels j-q represent the lower detection limit for antibody titer. When the detection value was below the lower detection limit, the antibody titer was calculated as the minimum detectable titer. Statistical significance (P value) was calculated by one-way ANOVA followed by Tukey’s test. *, P