{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T15:55:26Z","timestamp":1792598126557,"version":"4.5.0"},"reference-count":34,"publisher":"American Chemical Society (ACS)","issue":"41","license":[{"start":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22134003"],"award-info":[{"award-number":["22134003"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"Natural Science Foundation of Shanghai","doi-asserted-by":"publisher","award":["25ZR1403002"],"award-info":[{"award-number":["25ZR1403002"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Natural killer cell engagers (NKCEs) are promising immunotherapeutic agents for cancer treatment. However, their efficacy against solid tumors is severely limited by immune evasion mechanisms (mediated by the sialic acid\u2013Siglec axis and PD-1\/PD-L1 pathway), along with poor pharmacokinetics and off-target effects. Harnessing the precision and addressability of DNA origami, we engineered a tissue-specific, DNA origami-based, dual checkpoint-inhibiting NK synapse engager. This nanoplatform adopts a bilayered barrel architecture: the inner layer is functionalized with aNKp46, aPD-L1, and sialidase, while the outer layer is modified with the serum albumin-binding peptide ABD035 and a pH-sensitive i-motif switch. In the acidic tumor microenvironment, the DNA nanoengager undergoes specific dissociation of the outer protective layer, exposing the functional modules. These components concurrently bridge and activate NK cells, block the PD-L1 immune checkpoint, and specifically degrade tumor surface sialic acids, thereby reversing dual immunosuppression. This integrated DNA system enables synergistic integration of targeted activation, dual checkpoint blockade, and tumor microenvironment responsiveness, providing a novel smart nanoscale strategy to overcome multifaceted immune evasion in solid tumors and enhance the safety and efficacy of NK cell-based immunotherapy.<\/jats:p>","DOI":"10.1021\/jacs.6c15706","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T10:02:11Z","timestamp":1791799331000},"page":"45019-45031","source":"Crossref","is-referenced-by-count":0,"title":["A Tumor-Activatable\nDNA Nanoengager That Orchestrates\nNK Receptor Clustering and Immune Checkpoint Blockage to Enhance Antitumor\nCytotoxicity"],"prefix":"10.1021","volume":"148","author":[{"given":"Wen-Jia","family":"Shi","sequence":"first","affiliation":[{"name":"East China University of Science and Technology , , ,","place":["Shanghai, China, 200237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao-Qiang","family":"Li","sequence":"additional","affiliation":[{"name":"East China University of Science and Technology , , ,","place":["Shanghai, China, 200237"]},{"name":"Shihezi University , , ,","place":["Shihezi, China, 832003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Rong","family":"Lai","sequence":"additional","affiliation":[{"name":"East China University of Science and Technology , , ,","place":["Shanghai, China, 200237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Mei","family":"Li","sequence":"additional","affiliation":[{"name":"East China University of Science and Technology , , ,","place":["Shanghai, China, 200237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Juan","family":"Cheng","sequence":"additional","affiliation":[{"name":"East China University of Science and Technology , , ,","place":["Shanghai, China, 200237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wang","sequence":"additional","affiliation":[{"name":"East China University of Science and Technology , , ,","place":["Shanghai, China, 200237"]},{"name":"Shanghai Anshu Bio-tech., Co., Ltd. , ,","place":["Shanghai, China, 200030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Gao","sequence":"additional","affiliation":[{"name":"Central Hospital of Fengxian District , , ,","place":["Shanghai, China, 201400"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Qiang","family":"Ma","sequence":"additional","affiliation":[{"name":"East China University of Science and Technology , , ,","place":["Shanghai, China, 200237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5555-5359","authenticated-orcid":true,"given":"Bang-Ce","family":"Ye","sequence":"additional","affiliation":[{"name":"East China University of Science and Technology , , ,","place":["Shanghai, China, 200237"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,12]]},"reference":[{"key":"2026102111094677600_cit1","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1038\/s41586-023-06945-1","article-title":"Natural killer Cell Therapies","volume":"626","author":"Vivier","year":"2024","journal-title":"Nature"},{"key":"2026102111094677600_cit2","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1186\/s13045-015-0188-3","article-title":"AFM13: a First-in-class Tetravalent\nbispecific Anti-CD30\/CD16A Antibody for NK Cell-mediated Immunotherapy","volume":"8","author":"Wu","year":"2015","journal-title":"J. Hematol. Oncol."},{"key":"2026102111094677600_cit3","doi-asserted-by":"publisher","first-page":"8815","DOI":"10.1182\/blood-2022-169729","article-title":"The Novel\nBispecific Innate Cell Engager (ICE\u00ae) AFM28 Efficiently Directs\nAllogeneic NK Cells to CD123+Leukemic Stem- and Progenitor Cells in\nAML","volume":"140","author":"Schmitt","year":"2022","journal-title":"Blood"},{"key":"2026102111094677600_cit4","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1097\/CJI.0000000000000320","article-title":"BCMA-targeting Bispecific\nAntibody That Simultaneously Stimulates NKG2D-enhanced Efficacy Against\nMultiple Myeloma","volume":"43","author":"Wang","year":"2020","journal-title":"J. Immunother."},{"key":"2026102111094677600_cit5","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1158\/2326-6066.CIR-17-0649","article-title":"A CS1-NKG2D Bispecific Antibody Collectively\nActivates Cytolytic\nImmune Cells against Multiple Myeloma","volume":"6","author":"Chan","year":"2018","journal-title":"Cancer\nImmunol. Res."},{"key":"2026102111094677600_cit6","doi-asserted-by":"publisher","first-page":"1296","DOI":"10.1038\/s41587-022-01626-2","article-title":"Control of Acute Myeloid Leukemia\nby a Trifunctional NKp46-CD16a-NK Cell Engager Targeting CD123","volume":"41","author":"Gauthier","year":"2023","journal-title":"Nat. Biotechnol."},{"key":"2026102111094677600_cit7","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1158\/2326-6066.CIR-21-0843","article-title":"Exploiting Natural\nKiller Cell Engagers to Control Pediatric B-cell Precursor Acute Lymphoblastic\nLeukemia","volume":"10","author":"Colomar-Carando","year":"2022","journal-title":"Cancer Immunol. Res."},{"key":"2026102111094677600_cit8","doi-asserted-by":"publisher","first-page":"1701","DOI":"10.1016\/j.cell.2019.04.041","article-title":"Multifunctional Natural Killer Cell\nEngagers Targeting NKp46 Trigger Protective Tumor Immunity","volume":"177","author":"Gauthier","year":"2019","journal-title":"Cell"},{"key":"2026102111094677600_cit9","doi-asserted-by":"publisher","first-page":"1207276","DOI":"10.3389\/fimmu.2023.1207276","article-title":"Natural Killer\nCell Engagers (NKCEs):\na New Frontier in Cancer Immunotherapy","volume":"14","author":"Zhang","year":"2023","journal-title":"Front.\nImmunol."},{"key":"2026102111094677600_cit10","doi-asserted-by":"publisher","first-page":"1286750","DOI":"10.3389\/fimmu.2023.1286750","article-title":"Charting a Killer\nCourse to the Solid Tumor: Strategies\nto Recruit and Activate NK Cells in the Tumor Microenvironment","volume":"14","author":"Portillo","year":"2023","journal-title":"Front. Immunol."},{"key":"2026102111094677600_cit11","doi-asserted-by":"publisher","first-page":"164","DOI":"10.3390\/ijms23010164","article-title":"Challenges and Recent\nAdvances in NK Cell-Targeted Immunotherapies in Solid Tumors","volume":"23","author":"Lian","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"2026102111094677600_cit12","doi-asserted-by":"publisher","first-page":"669496","DOI":"10.3389\/fimmu.2021.669496","article-title":"Design of a Trispecific\nCheckpoint\nInhibitor and Natural Killer Cell Engager Based on a 2 + 1 Common\nLight Chain Antibody Architecture","volume":"12","author":"Bogen","year":"2021","journal-title":"Front. Immunol."},{"key":"2026102111094677600_cit13","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adh4379","article-title":"Siglec-7 Glyco-immune Binding mAbs or NK Cell Engager\nBiologics Induce Potent Antitumor Immunity against Ovarian Cancers","volume":"9","author":"Bordoloi","year":"2023","journal-title":"Sci. Adv."},{"key":"2026102111094677600_cit14","doi-asserted-by":"publisher","first-page":"1376","DOI":"10.1038\/s41589-020-0622-x","article-title":"Targeted Glycan Degradation Potentiates the Anticancer\nImmune Response In Vivo","volume":"16","author":"Gray","year":"2020","journal-title":"Nat. Chem. Biol."},{"key":"2026102111094677600_cit15","doi-asserted-by":"publisher","DOI":"10.1128\/msphere.01232-20","article-title":"Vibrio cholerae\nSialidase-Specific Immune Responses Are Associated with Protection\nagainst Cholera","volume":"6","author":"Kaisar","year":"2021","journal-title":"mSphere"},{"key":"2026102111094677600_cit16","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.00078-17","article-title":"Antibody against\nMicrobial Neuraminidases Recognizes Human Sialidase 3 (NEU3): the\nNeuraminidase\/Sialidase Superfamily Revisited","volume":"8","author":"Feng","year":"2017","journal-title":"mBio"},{"key":"2026102111094677600_cit17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-3-662-68816-8_49-1","article-title":"The Lytic Natural Killer Cell Immunological Synapse\nin Cancer","author":"Pereira Fernandes","year":"2025","journal-title":"Nat. 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Physiol."},{"key":"2026102111094677600_cit29","doi-asserted-by":"publisher","first-page":"3599","DOI":"10.1182\/blood-2012-04-425397","article-title":"NK Cell CD16\nSurface Expression and\nFunction Is Regulated by a Disintegrin and Metalloprotease-17 (ADAM17)","volume":"121","author":"Romee","year":"2013","journal-title":"Blood"},{"key":"2026102111094677600_cit30","doi-asserted-by":"publisher","first-page":"1883","DOI":"10.4049\/jimmunol.1300313","article-title":"Membrane-type\n6 Matrix Metalloproteinase\nRegulates the Activation-induced Downmodulation of CD16 in Human Primary\nNK Cells","volume":"191","author":"Peruzzi","year":"2013","journal-title":"J. Immunol."},{"key":"2026102111094677600_cit31","doi-asserted-by":"publisher","first-page":"101893","DOI":"10.1016\/j.smim.2024.101893","article-title":"Sialic Acid and Siglec Receptors\nin Tumor Immunity\nand Immunotherapy","volume":"74","author":"Mantuano","year":"2024","journal-title":"Semin. Immunol."},{"key":"2026102111094677600_cit32","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202509401","article-title":"Ultra-Fast\nIsothermal Formation of DNA Nanostructures in Culture Media: Application\nto In Situ Assembly of DNA Origami With Living Cells","volume":"22","author":"Bourdon","year":"2026","journal-title":"Small"},{"key":"2026102111094677600_cit33","doi-asserted-by":"publisher","first-page":"5312","DOI":"10.1021\/jacsau.5c00676","article-title":"Nick-and-Digest Strategy\nfor Programmable Circular ssDNA Production\nand Scalable DNA Origami Assembly","volume":"5","author":"Ye","year":"2025","journal-title":"JACS Au"},{"key":"2026102111094677600_cit34","doi-asserted-by":"publisher","first-page":"2550","DOI":"10.1016\/j.chempr.2024.04.023","article-title":"Programmable\nIn Vitro and In Vivo Folding of Single-stranded Nucleic-acid Wireframe\nOrigami","volume":"10","author":"Zhang","year":"2024","journal-title":"Chem"}],"container-title":["Journal of the American\nChemical Society"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jacs.6c15706","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/doi\/10.1021\/jacs.6c15706\/68818176\/jacs.6c15706.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/doi\/10.1021\/jacs.6c15706\/68818176\/jacs.6c15706.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T15:25:03Z","timestamp":1792596303000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jacsat\/article\/148\/41\/45019\/5448900\/A-Tumor-Activatable-DNA-Nanoengager-That"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,12]]},"references-count":34,"journal-issue":{"issue":"41","published-online":{"date-parts":[[2026,10,12]]},"published-print":{"date-parts":[[2026,10,21]]}},"URL":"https:\/\/doi.org\/10.1021\/jacs.6c15706","relation":{},"ISSN":["0002-7863","1520-5126"],"issn-type":[{"value":"0002-7863","type":"print"},{"value":"1520-5126","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,12]]}}}