{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T02:09:45Z","timestamp":1788487785963,"version":"build-2803163510"},"reference-count":37,"publisher":"National Academy of Sciences","issue":"45","license":[{"start":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T00:00:00Z","timestamp":1762128000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,11,11]]},"abstract":"<jats:p>\n                    Bispecific T cell engager (BiTE) therapeutics that link T cells and tumor cells to induce tumor cell lysis have demonstrated great success in the clinic for the treatment of many cancers. However, T cell exhaustion in the tumor microenvironment leads to tumor cell escape and BiTE therapy resistance. Herein, we developed a drug-loaded bispecific T cell nanoengager (NanoBiTE) to overcome this obstacle. NanoBiTE is composed of a mesoporous silica nanoparticle encapsulating the adenosine A2A receptor antagonist PBF-509 as a core, with a lipid layer surface coating as a shell and modification with anti-CD19 and anti-CD3 antibodies for tumor and T cell binding, respectively. Like the traditional BiTE blinatumomab, NanoBiTE can engage T cells with CD19\n                    <jats:sup>+<\/jats:sup>\n                    tumor cells to promote tumor cell lysis. However, unlike blinatumomab, which tends to induce T cell exhaustion, we showed that the release of PBF-509 from NanoBiTE suppressed the A2AR pathway and substantially improved tumor cell killing induced by NanoBiTE. Moreover, NanoBiTE treatment led to substantially reduced tumor burden in vivo in a humanized mouse model. Our results demonstrate that NanoBiTE is a safe and potent bispecific therapy that can also reduce T cell exhaustion for cancer immunotherapy.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2409564122","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T20:03:55Z","timestamp":1762200235000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":9,"title":["Drug-loaded bispecific T cell nanoengager overcomes T cell exhaustion for potent cancer immunotherapy"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8382-044X","authenticated-orcid":false,"given":"Jinjin","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xisha","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2503-4374","authenticated-orcid":false,"given":"Qiangqiang","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8475-9206","authenticated-orcid":false,"given":"Kelsey L.","family":"Swingle","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9810-5630","authenticated-orcid":false,"given":"Alex G.","family":"Hamilton","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningqiang","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania","place":["Philadelphia"]},{"name":"Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Science and Medicine, University of Science and Technology of China","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3628-2244","authenticated-orcid":false,"given":"Michael J.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania","place":["Philadelphia"]},{"name":"Penn Institute for RNA Innovation, University of Pennsylvania","place":["Philadelphia"]},{"name":"Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania","place":["Philadelphia"]},{"name":"Institute for Immunology, Perelman School of Medicine, University of Pennsylvania","place":["Philadelphia"]},{"name":"Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania","place":["Philadelphia"]},{"name":"Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,11,3]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-020-0347-5"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1609783"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-024-00896-6"},{"key":"e_1_3_4_4_2","first-page":"823","article-title":"First-in-class T cell engager approved for lung cancer","volume":"42","year":"2024","unstructured":"First-in-class T cell engager approved for lung cancer. 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