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Here, we demonstrate that microvilli insertion into nanopores robustly activates primary human T cells in the absence of TCR ligands, in a pore-size-dependent manner. Nanopores of \u223c240 nm in diameter elicit strong ERK phosphorylation, Ca2+ influx, and NFAT nuclear translocation, reaching levels comparable to biochemical stimulation using antibodies against the TCR complex and CD28. Although TCR knockdown attenuates responses, residual CD69 expression upon nanopore engagement indicates that nanoscale confinement lowers the activation threshold. Perturbation of membrane mechanics with GsMTx4 or methyl-\u03b2-cyclodextrin, as well as disruption of extracellular Ca2+-dependent interactions by EDTA, markedly impaired signaling, implicating extracellular calcium and membrane organization as key regulators of signaling. Together, these findings support a model in which \u223c240 nm-sized nanopores promote stable close-contact patches that seed TCR signaling. Finally, we show that nanoporous stimulation combined with CD28 costimulation activates patient-derived T cells comparably to conventional methods, highlighting a strategy with translational potential for immunotherapy.<\/jats:p>","DOI":"10.1021\/acsnano.5c16841","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T06:01:12Z","timestamp":1784700072000},"page":"20961-20978","source":"Crossref","is-referenced-by-count":2,"title":["Close Contacts Unlocked:\nNanopore-Stabilized Microvilli\nBypass T Cell Receptor\u2013Ligand-Dependent T Cell Activation"],"prefix":"10.1021","volume":"20","author":[{"given":"Tamara","family":"Zu\u0308nd","sequence":"first","affiliation":[{"name":"ETH Zu\u0308rich , , Gloriastrasse 37-39 , ,","place":["Zurich, Switzerland, 8092"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Lickert","sequence":"additional","affiliation":[{"name":"ETH Zu\u0308rich , , Gloriastrasse 37-39 , ,","place":["Zurich, Switzerland, 8092"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willi","family":"Weber","sequence":"additional","affiliation":[{"name":"Humboldt Universita\u0308t zu Berlin , , ,","place":["Berlin, Germany, 10099"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Saxer","sequence":"additional","affiliation":[{"name":"ETH Zu\u0308rich , , Gloriastrasse 37-39 , ,","place":["Zurich, Switzerland, 8092"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marius","family":"Wenk","sequence":"additional","affiliation":[{"name":"ETH Zu\u0308rich , , Gloriastrasse 37-39 , ,","place":["Zurich, Switzerland, 8092"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janina","family":"Zu\u0308nd","sequence":"additional","affiliation":[{"name":"ETH Zu\u0308rich , , Gloriastrasse 37-39 , ,","place":["Zurich, Switzerland, 8092"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8507-383X","authenticated-orcid":true,"given":"Tatiana","family":"Kovalchuk","sequence":"additional","affiliation":[{"name":"ETH Zu\u0308rich , , Gloriastrasse 37-39 , ,","place":["Zurich, Switzerland, 8092"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucrezia","family":"Baldi","sequence":"additional","affiliation":[{"name":"ETH Zu\u0308rich , , Gloriastrasse 37-39 , ,","place":["Zurich, Switzerland, 8092"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nozie D.","family":"Aghaizu","sequence":"additional","affiliation":[{"name":"Humboldt Universita\u0308t zu Berlin , , ,","place":["Berlin, Germany, 10099"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Daskalakis","sequence":"additional","affiliation":[{"name":"Inselspital, Bern University Hospital, University of Bern , , ,","place":["Bern, Switzerland, 3010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viola","family":"Vogel","sequence":"additional","affiliation":[{"name":"ETH Zu\u0308rich , , Gloriastrasse 37-39 , ,","place":["Zurich, Switzerland, 8092"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7577-9042","authenticated-orcid":true,"given":"Enrico","family":"Klotzsch","sequence":"additional","affiliation":[{"name":"Humboldt Universita\u0308t zu Berlin , , ,","place":["Berlin, Germany, 10099"]},{"name":"BIH Center for Regenerative Therapies (BCRT) , , Augustenburger Platz 1 , ,","place":["Berlin, Germany, 13353"]},{"name":"Helmholtz-Zentrum Hereon , , ,","place":["Teltow, Germany, 14513"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"issue":"4","key":"2026080409271624700_cit1","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1038\/ni908","article-title":"T Cell Fitness Determined\nby Signal Strength","volume":"4","author":"Gett","year":"2003","journal-title":"Nat. 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Eng."},{"key":"2026080409271624700_cit5","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202107373","article-title":"The Effect\nof the Nanoparticle Shape on T Cell Activation","volume":"18","author":"Oh","year":"2022","journal-title":"Small"},{"issue":"3","key":"2026080409271624700_cit6","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1038\/s41596-019-0249-0","article-title":"Activation and Expansion of Human\nT Cells Using Artificial Antigen-Presenting Cell Scaffolds","volume":"15","author":"Zhang","year":"2020","journal-title":"Nat. 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U.S.A."},{"key":"2026080409271624700_cit24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00713","article-title":"High-Affinity Ligands\nCan Trigger T Cell Receptor Signaling without CD45 Segregation","volume":"9","author":"Al-Aghbar","year":"2018","journal-title":"Front. Immunol."},{"issue":"1","key":"2026080409271624700_cit25","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38267-1","article-title":"Catch Bond Models May Explain How\nForce Amplifies TCR Signaling and Antigen Discrimination","volume":"14","author":"Choi","year":"2023","journal-title":"Nat. Commun."},{"key":"2026080409271624700_cit26","doi-asserted-by":"publisher","DOI":"10.1063\/5.0166848","article-title":"Mechanical\nForces Amplify TCR Mechanotransduction in T Cell Activation and Function","volume":"11","author":"Jeffreys","year":"2024","journal-title":"Appl. Phys. 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U.S.A."},{"issue":"40","key":"2026080409271624700_cit39","doi-asserted-by":"publisher","first-page":"E5916","DOI":"10.1073\/pnas.1605399113","article-title":"Three-Dimensional\nLocalization of T-Cell Receptors in Relation to Microvilli Using a\nCombination of Superresolution Microscopies","volume":"113","author":"Jung","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"10","key":"2026080409271624700_cit40","doi-asserted-by":"publisher","first-page":"3434","DOI":"10.1016\/j.celrep.2020.02.069","article-title":"ERM-Dependent Assembly of T Cell Receptor Signaling and Co-Stimulatory\nMolecules on Microvilli Prior to Activation","volume":"30","author":"Ghosh","year":"2020","journal-title":"Cell Rep."},{"key":"2026080409271624700_cit41","doi-asserted-by":"publisher","DOI":"10.1002\/pgr2.70040","article-title":"The Glycocalyx\u202f: Barriers and Opportunities\nat Cell \u2013 Cell Encounters","volume":"3","author":"Wyss","year":"2025","journal-title":"Proteoglycan\nRes."},{"issue":"9","key":"2026080409271624700_cit42","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.02187","article-title":"Surfing on Membrane Waves: Microvilli, Curved Membranes, and Immune\nSignaling","volume":"11","author":"Orbach","year":"2020","journal-title":"Front. Immunol."},{"issue":"1","key":"2026080409271624700_cit43","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-021-02995-1","article-title":"The Interplay\nbetween\nMembrane Topology and Mechanical Forces in Regulating T Cell Receptor\nActivity","volume":"5","author":"Al-Aghbar","year":"2022","journal-title":"Commun. Biol."},{"issue":"1","key":"2026080409271624700_cit44","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1016\/j.bbamem.2014.05.004","article-title":"Membrane Curvature\nModulation of Protein Activity Determined by NMR","volume":"1848","author":"Epand","year":"2015","journal-title":"Biochim. Biophys. Acta, Biomembr."},{"issue":"9","key":"2026080409271624700_cit45","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1038\/s41586-019-1499-2","article-title":"Force-Induced\nConformational Changes in PIEZO1","volume":"573","author":"Lin","year":"2019","journal-title":"Nature"},{"issue":"61","key":"2026080409271624700_cit46","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-022-01266-7","article-title":"Fluid Shear Stress Enhances T Cell Activation through\nPiezo1","volume":"20","author":"Hope","year":"2022","journal-title":"BMC Biol."},{"key":"2026080409271624700_cit47","doi-asserted-by":"crossref","unstructured":"Kotowski, M.; Heraghty, D. F.; Ko\u0308rbel, M.; Banik, D.; Zhang, Z.; Kedia, S.; Fu, B.; McColl, J.; Li, B.; Clarke, J.; Fellermeyer, M.; Lui, Y.; Bossi, G.; Cole, D. K.; Chen, H.; Basiarz, E.; Sharma, S.; Petsalaki, E.; Tape, C. J.; Wet, B. de.; Lee, S. F.; Santos, A. M.; Klenerman, D.; Davis, S. J.\n          T-Cell Signaling Relies on Partial\nCD45-Exclusion at Sub-Micron Sized Cellular Contacts\n          bioarxiv\n          2025.","DOI":"10.1101\/2025.08.29.673015"},{"issue":"13","key":"2026080409271624700_cit48","doi-asserted-by":"publisher","first-page":"5037","DOI":"10.1182\/blood-2008-04-149526","article-title":"Dendritic Cell Microvilli: A Novel Membrane Structure\nAssociated with the Multifocal Synapse and T-Cell Clustering","volume":"112","author":"Fisher","year":"2008","journal-title":"Blood"},{"issue":"11","key":"2026080409271624700_cit49","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1016\/j.it.2019.09.009","article-title":"Not All T\nCell Synapses Are Built the Same Way","volume":"40","author":"Kumari","year":"2019","journal-title":"Trends\nImmunol."},{"issue":"37","key":"2026080409271624700_cit50","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2404748121","article-title":"Mechanical Force Matters in Early\nT Cell Activation","volume":"121","author":"Fritzsche","year":"2024","journal-title":"Proc. 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