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Expanding the repertoire of clinically relevant LTRs could broaden the therapeutic potential of eTPD. Here we report trophoblast cell surface antigen\u20102 (TROP2), a clinically validated tumor\u2010associated antigen targeted by approved antibody\u2010drug conjugates, as a promising LTR for tumor cell\u2010selective eTPD. We develop TROP2\u2010targeting chimeras (TRTACs) by fusing a TROP2\u2010binding nanobody to target\u2010specific nanobodies. This fully genetically encoded, \u223c30\u00a0kDa nanobody format enables modular construction, broad target adaptability, and favorable tumor penetration. TRTACs induce degradation of diverse membrane proteins, including epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and programmed death\u2010ligand 1 (PD\u2010L1), preferentially in tumor cells rather than in nonmalignant cells. We further designed TRTAC\u2010drug conjugates (TRTAC\u2010DCs) by attaching cytotoxic payloads to TRTACs, enabling enhanced drug delivery together with protein degradation. The HER2\u2010targeted TRTAC\u2010DC reduced SKBR3 cell viability by 50% at 0.2\u00a0nM and showed potent antitumor activity in vivo, without significant body weight loss or histological abnormalities in major organs. These findings establish TROP2 as a clinically relevant LTR and provide a modular platform that combines tumor cell\u2010selective extracellular protein degradation with enhanced payload delivery.<\/jats:p>","DOI":"10.1002\/advs.77898","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["TROP2\u2010Targeting Chimeras (TRTACs) for Tumor Cell\u2010Selective Membrane Protein Degradation and Enhanced Drug Delivery"],"prefix":"10.1002","author":[{"given":"Luping","family":"Chen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioreactor Engineering East China University of Science and Technology  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinying","family":"Fu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioreactor Engineering East China University of Science and Technology  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqian","family":"Dong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioreactor Engineering East China University of Science and Technology  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobei","family":"Deng","sequence":"additional","affiliation":[{"name":"Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering College of Chemical and Biological Engineering Zhejiang University  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simin","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioreactor Engineering East China University of Science and Technology  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4914-6006","authenticated-orcid":false,"given":"Fujun","family":"Wang","sequence":"additional","affiliation":[{"name":"New Drug R&amp;D Center Zhejiang Fonow Medicine Co. Ltd.  Dongyang Zhejiang China"},{"name":"Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1574-5331","authenticated-orcid":false,"given":"Jian","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioreactor Engineering East China University of Science and Technology  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7029-3791","authenticated-orcid":false,"given":"Shiqun","family":"Shao","sequence":"additional","affiliation":[{"name":"Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering College of Chemical and Biological Engineering Zhejiang University  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9282-7205","authenticated-orcid":false,"given":"Liqiang","family":"Fan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioreactor Engineering East China University of Science and Technology  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioreactor Engineering East China University of Science and Technology  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixin","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioreactor Engineering East China University of Science and Technology  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573\u2010023\u201000833\u2010z"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adx5094"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1315"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010020\u20102545\u20109"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.3c08886"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202316089"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adf6249"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589\u2010021\u201000851\u20101"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.1c00146"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2022.12.003"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589\u2010021\u201000770\u20101"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010024\u201007947\u20103"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010024\u201052975\u20102"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2024.01.002"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12392"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010025\u201067207\u20104"},{"key":"e_1_2_10_18_1","doi-asserted-by":"crossref","unstructured":"C.Kougentakis M. 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