{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T02:23:12Z","timestamp":1790648592763,"version":"4.1.0"},"reference-count":84,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"35","funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["CBET-1605242"],"award-info":[{"award-number":["CBET-1605242"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R41GM153081-01"],"award-info":[{"award-number":["1R41GM153081-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21CA278468"],"award-info":[{"award-number":["R21CA278468"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32GM138826"],"award-info":[{"award-number":["T32GM138826"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32GM138826"],"award-info":[{"award-number":["T32GM138826"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000774","name":"Defense Threat Reduction Agency","doi-asserted-by":"publisher","award":["HDTRA1-20-10004"],"award-info":[{"award-number":["HDTRA1-20-10004"]}],"id":[{"id":"10.13039\/100000774","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UbiquiTx, Inc."},{"name":"Hartwell Foundation Postdoctoral Fellowship"}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,8,28]]},"abstract":"<jats:p>Aberrant activation of Wnt signaling results in unregulated accumulation of cytosolic \u03b2-catenin, which subsequently enters the nucleus and promotes transcription of genes that contribute to cellular proliferation and malignancy. Here, we sought to eliminate pathogenic \u03b2-catenin from the cytosol using designer ubiquibodies (uAbs), chimeric proteins composed of an E3 ubiquitin ligase and a target-binding domain that redirect intracellular proteins to the proteasome for degradation. To accelerate uAb development, we leveraged a protein language model\u2013driven algorithm called SaLT&amp;PepPr to computationally design \u201cguide\u201d peptides with affinity for \u03b2-catenin, which were subsequently fused to the catalytic domain of a human E3 called carboxyl terminus of Hsp70-interacting protein. Expression of the resulting peptide-guided uAbs in colorectal cancer cells led to the identification of several designs that greatly reduced the abnormally stable pool of free \u03b2-catenin in the cytosol and nucleus while preserving the normal membrane\u2013associated subpopulation. This selective knockdown of pathogenic \u03b2-catenin suppressed Wnt\/\u03b2-catenin signaling and impaired tumor cell survival and proliferation. Furthermore, one of the best degraders selectively decreased cytosolic but not membrane-associated \u03b2-catenin levels in livers of BALB\/c mice following delivery as a lipid nanoparticle\u2013encapsulated mRNA. Collectively, these findings reveal the unique ability of uAbs to selectively deplete abnormal proteins in vitro and in vivo and open the door to peptide-programmable biologic modulators of other disease-causing proteins.<\/jats:p>","DOI":"10.1126\/sciadv.aec8271","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T17:58:31Z","timestamp":1787939911000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["Programmable protein degraders enable selective knockdown of pathogenic \u03b2-catenin subpopulations in vitro and in vivo"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6678-7115","authenticated-orcid":true,"given":"Tianzheng","family":"Ye","sequence":"first","affiliation":[{"name":"Robert F. Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8198-0148","authenticated-orcid":true,"given":"Azmain","family":"Alamgir","sequence":"additional","affiliation":[{"name":"Robert F. Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cara M.","family":"Robertus","sequence":"additional","affiliation":[{"name":"Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0029-6983","authenticated-orcid":true,"given":"Darianna","family":"Colina","sequence":"additional","affiliation":[{"name":"Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY 14853, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5355-2843","authenticated-orcid":true,"given":"Connor","family":"Monticello","sequence":"additional","affiliation":[{"name":"Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas Connor","family":"Donahue","sequence":"additional","affiliation":[{"name":"Robert F. Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6273-8068","authenticated-orcid":true,"given":"Chandra","family":"Bandi","sequence":"additional","affiliation":[{"name":"Robert F. Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8531-1672","authenticated-orcid":true,"given":"Sophia","family":"Vincoff","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shrey","family":"Goel","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1965-5491","authenticated-orcid":true,"given":"Kieu","family":"Lam","sequence":"additional","affiliation":[{"name":"Genevant Sciences Corporation, 887 Great Northern Way, Vancouver, BC V5T 4T5, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9499-2028","authenticated-orcid":true,"given":"James","family":"Heyes","sequence":"additional","affiliation":[{"name":"Genevant Sciences Corporation, 887 Great Northern Way, Vancouver, BC V5T 4T5, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Putnam","sequence":"additional","affiliation":[{"name":"Robert F. Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA."},{"name":"Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2654-018X","authenticated-orcid":true,"given":"Christopher A.","family":"Alabi","sequence":"additional","affiliation":[{"name":"Robert F. Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA."},{"name":"Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3957-8478","authenticated-orcid":true,"given":"Pranam","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Computer and Information Science, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3226-1566","authenticated-orcid":true,"given":"Matthew P.","family":"DeLisa","sequence":"additional","affiliation":[{"name":"Robert F. Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA."},{"name":"Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA."},{"name":"Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY 14853, USA."},{"name":"Cornell Institute of Biotechnology, Cornell University, Ithaca, NY 14853, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.14.1.59"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.287.5458.1606"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.05.016"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2020227118"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2004.12.058"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.281.5382.1509"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/18884"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.10.5522"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg1427"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2006.12.007"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2018.06.003"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2013.233"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1593\/neo.07469"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-16-0309"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI0215429"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1517039112"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.3390\/genes13020319"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2004.10.012"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/aic.16854"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-024-00729-9"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09358-9"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41421-020-0171-1"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.544825"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2180"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.9b00127"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.9996"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07224-3"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00371-6"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-023-05464-z"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1021\/acssynbio.1c00357"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17022-w"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2199-4-10"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2133261100"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22969-5"},{"key":"e_1_3_2_36_2","first-page":"1151","article-title":"Targeting endogenous K-RAS for degradation through the affinity-directed protein missile system. Cell","volume":"27","author":"Roth S.","year":"2020","unstructured":"S. Roth, T. J. Macartney, A. Konopacka, K. H. Chan, H. Zhou, M. A. Queisser, G. P. Sapkota, Targeting endogenous K-RAS for degradation through the affinity-directed protein missile system. Cell. Chem. Biol. 27, 1151\u20131163.e6 (2020).","journal-title":"Chem. Biol."},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.0c01337"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-020-01470-7"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adr8638"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-025-02761-2"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.ade2574"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00330-0"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M511338200"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(03)00234-X"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a008052"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(03)00240-9"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50235-x"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M114.044016"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.032334"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt849"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.22785"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw385"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.275.5307.1787"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.082240999"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.4.1172-1183.2002"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21131"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2035389"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2034577"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1716153"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202209624"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2013.33"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2233012100"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.copbio.2022.102807"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2010.07737.x"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(02)02125-4"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1920251117"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-12-0650"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-1581"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1002\/cpch.37"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cobme.2023.100496"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4363"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-03-3906"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-213X-4-4"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.200900004"},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2015.08.007"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2023.06.023"},{"key":"e_1_3_2_77_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-02061-1"},{"key":"e_1_3_2_78_2","doi-asserted-by":"publisher","DOI":"10.1038\/d41573-026-00064-y"},{"key":"e_1_3_2_79_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mex.2015.11.001"},{"key":"e_1_3_2_80_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"e_1_3_2_81_2","doi-asserted-by":"publisher","DOI":"10.1021\/pr050300l"},{"key":"e_1_3_2_82_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M113.031591"},{"key":"e_1_3_2_83_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1318"},{"key":"e_1_3_2_84_2","doi-asserted-by":"publisher","DOI":"10.1002\/elps.200600524"},{"key":"e_1_3_2_85_2","doi-asserted-by":"publisher","DOI":"10.1002\/elps.201800042"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.aec8271","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T17:59:50Z","timestamp":1787939990000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.aec8271"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,28]]},"references-count":84,"journal-issue":{"issue":"35","published-print":{"date-parts":[[2026,8,28]]}},"alternative-id":["10.1126\/sciadv.aec8271"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.aec8271","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,28]]},"assertion":[{"value":"2025-10-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaec8271"}}