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Vaccines remain effective and are urgently needed despite immunosenescence. Self-assembling nanoparticles can enhance vaccine immunogenicity, but their translational use is constrained by the useless anticarrier immunity and carrier-induced epitope suppression (CIES). Herein, we developed a protective-antigen-based nanoparticle platform in which the PA chaperonin GroEL, an intrinsically self-assembling protective antigen, serves as the scaffold for a fusion immunogen reGroEL-PO, which displays the PcrV-OprI antigen (rePO). In mice, pre-existing anti-GroEL immunity did not blunt responses but enhanced anti-rePO immunity. Mechanistically, reGroEL-PO increased antigen uptake by antigen-presenting cells, promoted dendritic-cell maturation and accelerated both humoral and cellular immunity. In addition, reGroEL-PO elicited immune responses and conferred protection in adult and aged mice. These data demonstrate reGroEL-PO as a PA vaccine candidate and illustrate a nanoparticle design that leverages protective carriers and circumvents CIES effects.<\/jats:p>","DOI":"10.1021\/acsnano.6c04456","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T16:27:20Z","timestamp":1788280040000},"page":"26006-26026","source":"Crossref","is-referenced-by-count":0,"title":["Protective-Antigen\nScaffold Nanoparticle Vaccine Overcomes\nCarrier-Induced Suppression and Immunosenescence to Protect against\n                    <i>Pseudomonas aeruginosa<\/i>\n                    Pneumonia"],"prefix":"10.1021","volume":"20","author":[{"given":"Yuhang","family":"Li","sequence":"first","affiliation":[{"name":"Army Medical University , ; ,","place":["Chongqing, china, 400038"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhao","sequence":"additional","affiliation":[{"name":"Army Medical University , ; ,","place":["Chongqing, china, 400038"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meilin","family":"Wu","sequence":"additional","affiliation":[{"name":"Army Medical University , ; ,","place":["Chongqing, china, 400038"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Zeng","sequence":"additional","affiliation":[{"name":"Hubei Province Xuanen No.1 High School , ,","place":["Hubei, China, 445500"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Chongqing Yuanlun Biopharmaceuticals Inc , ,","place":["Chongqing, China, 400037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Xia","sequence":"additional","affiliation":[{"name":"Chongqing Yuanlun Biopharmaceuticals Inc , ,","place":["Chongqing, China, 400037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyi","family":"Li","sequence":"additional","affiliation":[{"name":"Army Medical University , ; ,","place":["Chongqing, china, 400038"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Cheng","sequence":"additional","affiliation":[{"name":"Army Medical University , ; ,","place":["Chongqing, china, 400038"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiqing","family":"Wan","sequence":"additional","affiliation":[{"name":"Army Medical University , ; ,","place":["Chongqing, china, 400038"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zifan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Army Medical University , ; ,","place":["Chongqing, china, 400038"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Army Medical University , ; ,","place":["Chongqing, china, 400038"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[{"name":"Army Medical University , , ,","place":["Shigatse, China, 857000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinglong","family":"Liu","sequence":"additional","affiliation":[{"name":"Army Medical University , ; ,","place":["Chongqing, china, 400038"]},{"name":"Army Medical University , , ,","place":["Chongqing, China, 400037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaling","family":"Liao","sequence":"additional","affiliation":[{"name":"Army Medical University , ; ,","place":["Chongqing, china, 400038"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongrong","family":"Cui","sequence":"additional","affiliation":[{"name":"Army Medical University , ; ,","place":["Chongqing, china, 400038"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Yang","sequence":"additional","affiliation":[{"name":"Chongqing Yuanlun Biopharmaceuticals Inc , ,","place":["Chongqing, China, 400037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Army Medical University , , ,","place":["Chongqing, China, 400038"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanming","family":"Zou","sequence":"additional","affiliation":[{"name":"Army Medical University , ; ,","place":["Chongqing, china, 400038"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8035-4551","authenticated-orcid":true,"given":"Jiang","family":"Gu","sequence":"additional","affiliation":[{"name":"Army Medical University , ; ,","place":["Chongqing, china, 400038"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"issue":"10325","key":"2026092909134504700_cit1","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/S0140-6736(21)02724-0","article-title":"Global burden of bacterial antimicrobial resistance in 2019: a systematic\nanalysis","volume":"399","year":"2022","journal-title":"Lancet (London, England)"},{"issue":"4","key":"2026092909134504700_cit2","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1007\/s15010-022-01973-x","article-title":"Outcomes of octogenarians and nonagenarians\nwith Pseudomonas aeruginosa bacteremia: a multicenter retrospective\nstudy","volume":"51","author":"Atamna","year":"2023","journal-title":"Infection"},{"issue":"4","key":"2026092909134504700_cit3","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.1007\/s15010-024-02452-1","article-title":"Incidence\nand resistance rates of Pseudomonas aeruginosa bloodstream infections\nin Switzerland: a nationwide surveillance study (2010\u20132022)","volume":"53","author":"Renggli","year":"2025","journal-title":"Infection"},{"issue":"4","key":"2026092909134504700_cit4","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1038\/7391","article-title":"Active and passive\nimmunization with the Pseudomonas V antigen protects against type\nIII intoxication and lung injury","volume":"5","author":"Sawa","year":"1999","journal-title":"Nature medicine"},{"issue":"1","key":"2026092909134504700_cit5","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1038\/s41541-023-00672-4","article-title":"Strong immune responses\nand protection of PcrV and OprF-I mRNA vaccine candidates against\nPseudomonas aeruginosa","volume":"8","author":"Wang","year":"2023","journal-title":"npj Vaccines"},{"key":"2026092909134504700_cit6","doi-asserted-by":"publisher","first-page":"116264","DOI":"10.1016\/j.biopha.2024.116264","article-title":"Enhanced protective\nefficacy of an\nOprF\/PcrV bivalent DNA vaccine against Pseudomonas aeruginosa using\na hydrogel delivery system","volume":"172","author":"Zhang","year":"2024","journal-title":"Biomedicine &\npharmacotherapy = Biomedecine & pharmacotherapie"},{"issue":"12","key":"2026092909134504700_cit7","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1111\/1348-0421.12658","article-title":"The protective\neffects of nasal PcrV-CpG oligonucleotide vaccination against Pseudomonas\naeruginosa pneumonia","volume":"62","author":"Naito","year":"2018","journal-title":"Microbiol. Immunol."},{"key":"2026092909134504700_cit8","doi-asserted-by":"publisher","first-page":"601601","DOI":"10.3389\/fimmu.2020.601601","article-title":"Development of a Chimeric\nVaccine\nAgainst Pseudomonas aeruginosa Based on the Th17-Stimulating Epitopes\nof PcrV and AmpC","volume":"11","author":"Wang","year":"2021","journal-title":"Front. Immunol."},{"issue":"1","key":"2026092909134504700_cit9","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1186\/s13054-022-04204-9","article-title":"Safety, efficacy, and\npharmacokinetics of gremubamab (MEDI3902), an anti-Pseudomonas aeruginosa\nbispecific human monoclonal antibody, in P. aeruginosa-colonised,\nmechanically ventilated intensive care unit patients: a randomised\ncontrolled trial","volume":"26","author":"Chastre","year":"2022","journal-title":"Critical care (London, England)"},{"issue":"1","key":"2026092909134504700_cit10","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1186\/s13054-020-2792-z","article-title":"Efficacy, immunogenicity, and safety\nof IC43 recombinant Pseudomonas aeruginosa vaccine in mechanically\nventilated intensive care patients-a randomized clinical trial","volume":"24","author":"Adlbrecht","year":"2020","journal-title":"Critical care (London, England)"},{"issue":"1","key":"2026092909134504700_cit11","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1038\/s41392-024-01846-9","article-title":"Safety, immunogenicity\nand protective effect of sequential vaccination with inactivated and\nrecombinant protein COVID-19 vaccine in the elderly: a prospective\nlongitudinal study","volume":"9","author":"Liu","year":"2024","journal-title":"Signal Transduction Targeted\nTher."},{"issue":"1","key":"2026092909134504700_cit12","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1038\/s43587-022-00343-4","article-title":"Impaired CD4(+) T cell\nresponse in older adults is associated with reduced immunogenicity\nand reactogenicity of mRNA COVID-19 vaccination","volume":"3","author":"Jo","year":"2023","journal-title":"Nat. Aging"},{"issue":"12","key":"2026092909134504700_cit13","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1016\/j.molmed.2022.09.008","article-title":"How aging\nimpacts vaccine efficacy:\nknown molecular and cellular mechanisms and future directions","volume":"28","author":"Chen","year":"2022","journal-title":"Trends Mol. Med."},{"issue":"9","key":"2026092909134504700_cit14","doi-asserted-by":"publisher","first-page":"1095","DOI":"10.1586\/erv.10.89","article-title":"Nano-microparticles\nas immune adjuvants:\ncorrelating particle sizes and the resultant immune responses","volume":"9","author":"Oyewumi","year":"2010","journal-title":"Expert Rev. Vaccines"},{"issue":"5","key":"2026092909134504700_cit15","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1016\/j.ejps.2011.10.012","article-title":"Synthesis\nof a novel kind of carbon nanoparticle with large mesopores and macropores\nand its application as an oral vaccine adjuvant","volume":"44","author":"Wang","year":"2011","journal-title":"European journal of pharmaceutical sciences: official journal of\nthe European Federation for Pharmaceutical Sciences"},{"issue":"1","key":"2026092909134504700_cit16","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.vaccine.2012.10.083","article-title":"Virus-like particles as a highly\nefficient vaccine platform: diversity of targets and production systems\nand advances in clinical development","volume":"31","author":"Kushnir","year":"2012","journal-title":"Vaccine"},{"issue":"11","key":"2026092909134504700_cit17","doi-asserted-by":"publisher","first-page":"1674","DOI":"10.1016\/j.vaccine.2009.01.005","article-title":"The influence of carrier protein\non the immunogenicity of simultaneously administered conjugate vaccines\nin infants","volume":"27","author":"Po\u0308llabauer","year":"2009","journal-title":"Vaccine"},{"issue":"2","key":"2026092909134504700_cit18","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1128\/iai.61.2.432-438.1993","article-title":"Non-epitope-specific\nsuppression of the antibody response to Haemophilus influenzae type\nb conjugate vaccines by preimmunization with vaccine components","volume":"61","author":"Barington","year":"1993","journal-title":"Infect. Immun."},{"key":"2026092909134504700_cit19","doi-asserted-by":"publisher","DOI":"10.1016\/j.eng.2022.12.007","article-title":"Lung-Targeted Transgene Expression of Nanocomplexed\nAd5 Enhances\nImmune Response in the Presence of Preexisting Immunity","author":"Yang","year":"2023","journal-title":"Engineering"},{"issue":"7","key":"2026092909134504700_cit20","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.1038\/s41591-020-0911-7","article-title":"IgG-cleaving endopeptidase enables\nin vivo gene therapy in the presence of anti-AAV neutralizing antibodies","volume":"26","author":"Leborgne","year":"2020","journal-title":"Nature medicine"},{"issue":"10","key":"2026092909134504700_cit21","doi-asserted-by":"publisher","first-page":"100780","DOI":"10.1016\/j.xcrm.2022.100780","article-title":"Antigen-\nand scaffold-specific antibody responses to protein nanoparticle immunogens","volume":"3","author":"Kraft","year":"2022","journal-title":"Cell Rep. Med."},{"issue":"1","key":"2026092909134504700_cit22","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/s41564-025-02209-y","article-title":"A Plasmodium-derived nanoparticle vaccine elicits sterile\nprotection against malaria in mice","volume":"11","author":"Shi","year":"2026","journal-title":"Nat. Microbiol."},{"issue":"37","key":"2026092909134504700_cit23","doi-asserted-by":"publisher","first-page":"18550","DOI":"10.1073\/pnas.1901340116","article-title":"Excessive\nCD11c(+)Tbet(+) B cells promote aberrant T(FH) differentiation and\naffinity-based germinal center selection in lupus","volume":"116","author":"Zhang","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"6","key":"2026092909134504700_cit24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0253084","article-title":"GroEL is an\nimmunodominant surface-exposed\nantigen of Rickettsia typhi","volume":"16","author":"Rauch","year":"2021","journal-title":"PLoS One"},{"issue":"8","key":"2026092909134504700_cit25","doi-asserted-by":"publisher","first-page":"3389","DOI":"10.1128\/IAI.00143-09","article-title":"Mycobacterium tuberculosis Cpn60.2\nand DnaK are located\non the bacterial surface, where Cpn60.2 facilitates efficient bacterial\nassociation with macrophages","volume":"77","author":"Hickey","year":"2009","journal-title":"Infect. Immun."},{"issue":"4","key":"2026092909134504700_cit26","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1111\/brv.12037","article-title":"Chaperonin\n60: a paradoxical, evolutionarily\nconserved protein family with multiple moonlighting functions","volume":"88","author":"Henderson","year":"2013","journal-title":"Biological reviews of the Cambridge Philosophical Society"},{"issue":"1","key":"2026092909134504700_cit27","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1038\/s41541-022-00562-1","article-title":"Bordetella pertussis\nwhole cell immunization protects\nagainst Pseudomonas aeruginosa infections","volume":"7","author":"Blackwood","year":"2022","journal-title":"npj\nVaccines"},{"issue":"16","key":"2026092909134504700_cit28","doi-asserted-by":"publisher","first-page":"2035","DOI":"10.1016\/j.vaccine.2013.02.045","article-title":"Recombinant\nheat shock protein 60 (Hsp60\/GroEL) of Salmonella enterica serovar\nTyphi elicits cross-protection against multiple bacterial pathogens\nin mice","volume":"31","author":"Chitradevi","year":"2013","journal-title":"Vaccine"},{"issue":"1","key":"2026092909134504700_cit29","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1111\/j.1574-695X.2009.00548.x","article-title":"Immunogenicity\nand protective efficacy of GroEL (hsp60) of Streptococcus pneumoniae\nagainst lethal infection in mice","volume":"56","author":"Khan","year":"2009","journal-title":"FEMS Immunol.\nMed. Microbiol."},{"issue":"1\u20133","key":"2026092909134504700_cit30","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1016\/j.molimm.2010.08.001","article-title":"GroEL provides protection against Bacillus anthracis\ninfection in BALB\/c mice","volume":"48","author":"Sinha","year":"2010","journal-title":"Mol. Immunol."},{"issue":"12","key":"2026092909134504700_cit31","doi-asserted-by":"publisher","first-page":"3281","DOI":"10.1039\/D5BM01792K","article-title":"Silica-coated papillomavirus-based\nnanoparticles: a shielded scaffold for HIV-1 vaccines","volume":"14","author":"Wang","year":"2026","journal-title":"Biomater. Sci."},{"issue":"2","key":"2026092909134504700_cit32","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1086\/314590","article-title":"Self heat-shock\nprotein (hsp60) peptide serves in a conjugate vaccine against a lethal\npneumococcal infection","volume":"179","author":"Ko\u0308nen-Waisman","year":"1999","journal-title":"J. Infect. Dis."},{"issue":"7","key":"2026092909134504700_cit33","doi-asserted-by":"publisher","first-page":"1618","DOI":"10.1016\/j.immuni.2024.05.009","article-title":"Opposing effects\nof pre-existing antibody and memory\nT cell help on the dynamics of recall germinal centers","volume":"57","author":"Schiepers","year":"2024","journal-title":"Immunity"},{"issue":"6427","key":"2026092909134504700_cit34","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1126\/science.aat9120","article-title":"Innate\nimmune recognition of glycans targets HIV nanoparticle immunogens\nto germinal centers","volume":"363","author":"Tokatlian","year":"2019","journal-title":"Science (New York, N.Y.)"},{"issue":"6","key":"2026092909134504700_cit35","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1016\/S1473-3099(13)70046-X","article-title":"AS03-adjuvanted\nversus non-adjuvanted inactivated trivalent influenza vaccine against\nseasonal influenza in elderly people: a phase 3 randomised trial","volume":"13","author":"McElhaney","year":"2013","journal-title":"Lancet Infect. Dis."},{"issue":"13","key":"2026092909134504700_cit36","doi-asserted-by":"publisher","first-page":"1504","DOI":"10.1016\/j.vaccine.2016.02.021","article-title":"Protective role of Th17 cells in\npulmonary infection","volume":"34","author":"Rathore","year":"2016","journal-title":"Vaccine"},{"issue":"4","key":"2026092909134504700_cit37","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1038\/s41568-024-00785-5","article-title":"Cross-priming in cancer\nimmunology\nand immunotherapy","volume":"25","author":"Luri-Rey","year":"2025","journal-title":"Nat. Rev. Cancer"},{"issue":"2","key":"2026092909134504700_cit38","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.jinf.2016.11.008","article-title":"Intensive\ncare unit-acquired pneumonia due to Pseudomonas\naeruginosa with and without multidrug resistance","volume":"74","author":"Ferna\u0301ndez-Barat","year":"2017","journal-title":"J. Infect."},{"issue":"2","key":"2026092909134504700_cit39","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.jhin.2019.06.005","article-title":"Incremental\nclinical\nand economic burden of suspected respiratory infections due to multi-drug-resistant\nPseudomonas aeruginosa in the United States","volume":"103","author":"Tabak","year":"2019","journal-title":"J. Hosp. Infect."},{"issue":"11","key":"2026092909134504700_cit40","doi-asserted-by":"publisher","first-page":"1602","DOI":"10.1513\/AnnalsATS.201506-333OC","article-title":"A Comprehensive\nAnalysis of the Impact of Pseudomonas aeruginosa Colonization on Prognosis\nin Adult Bronchiectasis","volume":"12","author":"Finch","year":"2015","journal-title":"Ann. Am. Thorac. Soc."},{"issue":"11","key":"2026092909134504700_cit41","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1012696","article-title":"Mucosal immunization\nwith the lung Lactobacillus-derived amphiphilic exopolysaccharide\nadjuvanted recombinant vaccine improved protection against P. aeruginosa\ninfection","volume":"20","author":"Zhang","year":"2024","journal-title":"PLoS Pathog."},{"key":"2026092909134504700_cit42","doi-asserted-by":"publisher","first-page":"2497","DOI":"10.3389\/fimmu.2019.02497","article-title":"Intranasal Peptide-Based\nFpvA-KLH Conjugate Vaccine Protects Mice From Pseudomonas aeruginosa\nAcute Murine Pneumonia","volume":"10","author":"Sen-Kilic","year":"2019","journal-title":"Front. Immunol."},{"key":"2026092909134504700_cit43","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2026.06.029","article-title":"A novel\ncystic fibrosis-mimetic Pseudomonas auxotrophic vaccine is protective\nin vivo and is associated with IL-17\/IgA mucosal Immunity","author":"Sereme","year":"2026","journal-title":"Molecular therapy: the journal of the American Society of\nGene Therapy"},{"issue":"36","key":"2026092909134504700_cit44","doi-asserted-by":"publisher","DOI":"10.1128\/mra.00653-20","article-title":"Complete Genome Sequence\nof Pseudomonas aeruginosa XN-1, Isolated from the Sputum of a Severe\nPneumonia Patient","volume":"9","author":"Gao","year":"2020","journal-title":"Microbiol. Resour. 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