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However, many cancer vaccine systems still preferentially induce transient effector CD8+ T-cell responses with limited capacity to sustain checkpoint-responsive immunity. Here, we report NIRVax, a second near-infrared window (NIR-II)-traceable, long-residence nanovaccine that couples real-time in vivo tracking to programmable systemic antigen residence. NIRVax is assembled from a triphenylamine-based NIR-II fluorophore and distearoyl phosphoethanolamine-polyethylene glycol 2000 (DSPE-PEG2000), followed by covalent conjugation of the model protein antigen ovalbumin (OVA). After intravenous administration, NIRVax sustains antigen residence across secondary lymphoid organs (SLOs), with lymphoid signals peaking at day 4 postinjection followed by gradual clearance. This material residence profile enhances antigen uptake, dendritic cell maturation, and stem-like CD8+ T-cell generation. NIRVax also accumulates at bone-associated sites, where it is associated with hematopoietic remodeling, myeloid-biased differentiation, and a reduced suppressive myeloid output. Functionally, systemic NIRVax vaccination establishes antigen-specific progenitor-exhausted CD8+ T-cell (TPEX) reservoirs across lymphoid tissues and the tumor microenvironment (TME). Upon programmed death-ligand 1 (PD-L1) blockade, these reservoirs are mobilized into effector CD8+ T-cell responses, leading to tumor immune remodeling, epitope spreading, and improved melanoma control. These findings establish spatiotemporal antigen residence as an engineerable biomaterial parameter for shaping the CD8+ T-cell fate and provide a NIR-II-traceable nanovaccine strategy for potentiating checkpoint cancer immunotherapy.<\/jats:p>","DOI":"10.1021\/acsnano.6c12073","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:05:53Z","timestamp":1790831153000},"page":"27372-27389","source":"Crossref","is-referenced-by-count":0,"title":["An NIR-II-Traceable\nNanovaccine Programs Systemic\nAntigen Residence to Establish Checkpoint-Responsive Progenitor-Exhausted\nCD8-Positive T-Cell Reservoirs for Effective Cancer Immunotherapy"],"prefix":"10.1021","volume":"20","author":[{"given":"Muye","family":"Ma","sequence":"first","affiliation":[{"name":"National University of Singapore , , ,","place":["Singapore, Singapore, 117597"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiqiang","family":"Xie","sequence":"additional","affiliation":[{"name":"Xiamen University , , ,","place":["Xiamen, China, 361102"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Zhang","sequence":"additional","affiliation":[{"name":"National University of Singapore , , ,","place":["Singapore, Singapore, 117543"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoran","family":"Ma","sequence":"additional","affiliation":[{"name":"National University of Singapore , , ,","place":["Singapore, Singapore, 117543"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wang","sequence":"additional","affiliation":[{"name":"National University of Singapore , , ,","place":["Singapore, Singapore, 117543"]},{"name":"Hunan University , , ,","place":["Changsha, China, 410082"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Wang","sequence":"additional","affiliation":[{"name":"National University of Singapore , , ,","place":["Singapore, Singapore, 117543"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihao","family":"Zhao","sequence":"additional","affiliation":[{"name":"National University of Singapore , , ,","place":["Singapore, Singapore, 117543"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huize","family":"Han","sequence":"additional","affiliation":[{"name":"National University of Singapore , , ,","place":["Singapore, Singapore, 117543"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongliang","family":"Zhang","sequence":"additional","affiliation":[{"name":"National University of Singapore , , ,","place":["Singapore, Singapore, 117597"]},{"name":"National University of Singapore , , ,","place":["Singapore, Singapore, 117597"]},{"name":"National University of Singapore , , ,","place":["Singapore, Singapore, 117597"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9779-2662","authenticated-orcid":true,"given":"Jianjun","family":"He","sequence":"additional","affiliation":[{"name":"Hunan University , , ,","place":["Changsha, China, 410082"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Tian","sequence":"additional","affiliation":[{"name":"Xiamen University , , ,","place":["Xiamen, China, 361102"]},{"name":"Xiamen University , , ,","place":["Xiamen, China, 361102"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8613-4285","authenticated-orcid":true,"given":"Wei","family":"Tang","sequence":"additional","affiliation":[{"name":"National University of Singapore , , ,","place":["Singapore, Singapore, 117597"]},{"name":"National University of Singapore , , ,","place":["Singapore, Singapore, 117543"]},{"name":"Agency for Science, Technology and Research (A*STAR) , , ,","place":["Singapore, Singapore, 138648"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"issue":"7","key":"2026101310103379400_cit1","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1038\/s41573-021-00345-8","article-title":"The foundations of immune checkpoint\nblockade and the ipilimumab approval decennial","volume":"21","author":"Korman","year":"2022","journal-title":"Nat. Rev. Drug Discovery"},{"issue":"6","key":"2026101310103379400_cit2a","doi-asserted-by":"publisher","first-page":"924","DOI":"10.1038\/s43018-025-00986-3","article-title":"The tumor\nmicroenvironment\u2019s role in the response to immune checkpoint\nblockade","volume":"6","author":"Aliazis","year":"2025","journal-title":"Nat. Cancer"},{"issue":"5","key":"2026101310103379400_cit2b","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1038\/s41577-024-01111-8","article-title":"Cancer immune evasion, immunoediting\nand intratumour heterogeneity","volume":"25","author":"Roerden","year":"2025","journal-title":"Nat. Rev. Immunol."},{"issue":"11","key":"2026101310103379400_cit3","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1038\/s41568-023-00615-0","article-title":"Stem-like exhausted and memory CD8+\nT cells in cancer","volume":"23","author":"Gebhardt","year":"2023","journal-title":"Nat. Rev. Cancer"},{"issue":"1","key":"2026101310103379400_cit4","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.immuni.2018.12.021","article-title":"Intratumoral\nTcf1+PD-1+CD8+ T Cells with Stem-like Properties Promote Tumor Control\nin Response to Vaccination and Checkpoint Blockade Immunotherapy","volume":"50","author":"Siddiqui","year":"2019","journal-title":"Immunity"},{"issue":"1","key":"2026101310103379400_cit5","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.trecan.2025.09.004","article-title":"Reprogramming T cell stemness against\ncancer","volume":"12","author":"Wang","year":"2026","journal-title":"Trends Cancer"},{"issue":"1","key":"2026101310103379400_cit6a","doi-asserted-by":"publisher","first-page":"3522","DOI":"10.1038\/s41467-025-58510-1","article-title":"Combination radiation\nand \u03b1PD-L1 enhance tumor control by stimulating CD8+ PD-1+ TCF-1+\nT cells in the tumor-draining lymph node","volume":"16","author":"Shen","year":"2025","journal-title":"Nat.\nCommun."},{"issue":"8","key":"2026101310103379400_cit6b","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1038\/s41590-025-02219-2","article-title":"Lymph-node-derived\nstem-like but not tumor-tissue-resident CD8+ T cells fuel anticancer\nimmunity","volume":"26","author":"Wijesinghe","year":"2025","journal-title":"Nat. Immunol."},{"issue":"86","key":"2026101310103379400_cit7","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adg0539","article-title":"PD-1 blockade\nincreases the self-renewal of stem-like\nCD8 T cells to compensate for their accelerated differentiation into\neffectors","volume":"8","author":"Gill","year":"2023","journal-title":"Sci. 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Immunol."},{"issue":"8059","key":"2026101310103379400_cit13","doi-asserted-by":"publisher","first-page":"772","DOI":"10.1038\/s41586-024-08562-y","article-title":"An early precursor CD8+\nT cell that adapts to acute\nor chronic viral infection","volume":"640","author":"McManus","year":"2025","journal-title":"Nature"},{"issue":"1","key":"2026101310103379400_cit14a","doi-asserted-by":"publisher","first-page":"9175","DOI":"10.1038\/s41467-025-64107-5","article-title":"A pan-immunotherapy\nsignature to predict intratumoral CD8+ T cell\nexpansions","volume":"16","author":"Takahashi","year":"2025","journal-title":"Nat. Commun."},{"issue":"12","key":"2026101310103379400_cit14b","doi-asserted-by":"publisher","first-page":"2312","DOI":"10.1038\/s41590-025-02316-2","article-title":"Transcriptional\nregulator SATB1 limits CD8+ T cell population expansion and effector\ndifferentiation in chronic infection and cancer","volume":"26","author":"Heyden","year":"2025","journal-title":"Nat. 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Bioeng."},{"issue":"1","key":"2026101310103379400_cit21b","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1186\/s12951-023-01977-1","article-title":"Targeting lymph node\ndelivery with nanovaccines for cancer immunotherapy: recent advances\nand future directions","volume":"21","author":"Li","year":"2023","journal-title":"J. Nanobiotechnol."},{"issue":"9","key":"2026101310103379400_cit22","doi-asserted-by":"publisher","first-page":"2847","DOI":"10.1016\/j.matt.2022.06.030","article-title":"Molecular\nengineering of AIE luminogens for NIR-II\/IIb bioimaging and surgical\nnavigation of lymph nodes","volume":"5","author":"Song","year":"2022","journal-title":"Matter"},{"issue":"8","key":"2026101310103379400_cit23","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":"2026101310103379400_cit24a","doi-asserted-by":"publisher","first-page":"113945","DOI":"10.1016\/j.jconrel.2025.113945","article-title":"Impact of ionizable lipid type on\nthe pharmacokinetics and biodistribution of mRNA-lipid nanoparticles\nafter intravenous and subcutaneous injection","volume":"384","author":"Ren","year":"2025","journal-title":"J. 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Immunol."},{"issue":"9","key":"2026101310103379400_cit25b","doi-asserted-by":"publisher","first-page":"101046","DOI":"10.1016\/j.mcpro.2025.101046","article-title":"Structural\nInsights Into Complement Inhibition: Visualizing Distinct Binding\nModes of C4b-Binding Protein Complexes With C4b and SAP","volume":"24","author":"Kadava\u0301","year":"2025","journal-title":"Mol. Cell. Proteomics"},{"issue":"1","key":"2026101310103379400_cit25c","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1186\/s12951-025-03565-x","article-title":"Engineered protein corona sustains\nstealth functionality of nanocarriers in plasma","volume":"23","author":"Zhang","year":"2025","journal-title":"J. Nanobiotechnol."},{"issue":"41","key":"2026101310103379400_cit26a","doi-asserted-by":"publisher","first-page":"2301686","DOI":"10.1002\/adma.202301686","article-title":"Tuning the Organ Tropism\nof Polymersome for Spleen-Selective Nanovaccine Delivery to Boost\nCancer Immunotherapy","volume":"35","author":"Gu","year":"2023","journal-title":"Adv. Mater."},{"issue":"10","key":"2026101310103379400_cit26b","doi-asserted-by":"publisher","first-page":"1802199","DOI":"10.1002\/advs.201802199","article-title":"Prevention of Dominant IgG Adsorption\non Nanocarriers in IgG-Enriched Blood Plasma by Clusterin Precoating","volume":"6","author":"Prozeller","year":"2019","journal-title":"Adv. Sci."},{"issue":"5","key":"2026101310103379400_cit27","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1208\/s12248-021-00630-9","article-title":"The Nano-War Against Complement Proteins","volume":"23","author":"Wang","year":"2021","journal-title":"AAPS J."},{"key":"2026101310103379400_cit28a","doi-asserted-by":"publisher","first-page":"567365","DOI":"10.3389\/fimmu.2020.567365","article-title":"Opsonins and\nDysopsonins of Nanoparticles: Facts, Concepts, and Methodological\nGuidelines","volume":"11","author":"Papini","year":"2020","journal-title":"Front. 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