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Here, we develop an engineered dendritic cell\u2013derived small extracellular vesicle (DC-sEV) nanoplatform for combinatorial immunotherapy via\n                  <jats:italic>in situ<\/jats:italic>\n                  T-cell activation and checkpoint reprogramming. DC-sEVs preserve intrinsic dendritic-cell immunobiology, enabling antigen presentation and potent T-cell activation. We further integrate high-efficiency cargo loading and membrane functionalization to selectively deliver ICB payloads to T cells, achieving dual reprogramming that sustains effector function and amplifies antitumor immunity. This approach reduced cancer cell viability to 44.05%\n                  <jats:italic>in vitro<\/jats:italic>\n                  and produced 82.12% tumor growth inhibition\n                  <jats:italic>in vivo<\/jats:italic>\n                  , establishing DC-sEVs as a targeted, scalable cell-free immunotherapy platform.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>HIGHLIGHTS<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>DC-sEVs preserve antigen presentation, T-cell activation, and lymph node targeting<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Chirality-assisted loading with pH-responsive functionalization enables efficient cytosolic delivery while maintaining membrane bioactivity<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Engineered DC-sEVs combine in situ T-cell priming and PD-1 silencing to enhance effector function<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>In situ T-cell reprogramming drives potent antitumor efficacy and favorable tumor microenvironment remodeling<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>GRAPHICAL ABSTRACT<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" fig-type=\"figure\" orientation=\"portrait\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"717283v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.08.717283","type":"posted-content","created":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T05:50:11Z","timestamp":1775973011000},"source":"Crossref","is-referenced-by-count":0,"title":["Dual-Engineered Dendritic Cell\u2013Derived Small Extracellular Vesicles Couple T-Cell Priming with Checkpoint Reprogramming for Synergistic Immunotherapy"],"prefix":"10.64898","author":[{"given":"Gaeun","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA"},{"name":"Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runyao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Webber","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, USA"},{"name":"Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4353-6660","authenticated-orcid":false,"given":"Yichun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA"},{"name":"Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041510550719000_2026.04.08.717283v1.1","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1038\/s41577-022-00719-y","article-title":"Tumour immunotherapy: lessons from predator\u2013prey theory","volume":"22","year":"2022","journal-title":"Nat. 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