{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T20:08:18Z","timestamp":1789070898440,"version":"build-2803163510"},"posted":{"date-parts":[[2026,9,7]]},"group-title":"Cell Biology","reference-count":21,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH\/NIBIB"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Targeted protein degradation (TPD) has been highly effective for intracellular targets, but extending this approach to extracellular and membrane-bound proteins remains difficult because most extracellular TPD (eTPD) strategies depend on ligand-targeting receptors (LTRs) whose expression and recycling vary across tissues. Existing LTR-independent, multivalent platforms expand the scope of eTPDs by eliminating this dependence on LTRs and enabling cancer-selective designs. Layering in an additional degree of selectivity through endogenously activatable triggers, such as overexpressed enzymes, can enhance the tissue tropism of the LTR-independent platforms and widen therapeutic window. Here we report triggerable polymeric lysosome targeting chimeras (tPolyTACs), which combine antibody-defined targeting with locally triggered covalent capture. tPolyTACs conjugate monoclonal antibodies to phosphatase-cleavable substrates that, upon engagement of endogenous cell-surface phosphatases, unmask a reactive quinone methide electrophile, covalently trapping the target complex and driving its clathrin-mediated internalization and autolysosomal degradation. We show tPolyTAC-mediated degradation of the membrane proteins EGFR, PD-L1, and cMET, and demonstrate that para-substituted electrophiles outperform ortho-substituted analogues likely due to more favorable active-site positioning. These results establish tPoly-TACs as a modular, covalent, enzyme-responsive platform that resolves the efficiency-selectivity trade-off limitations in extracellular degradation.<\/jats:p>","DOI":"10.64898\/2026.09.03.749226","type":"posted-content","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T21:00:16Z","timestamp":1788814816000},"source":"Crossref","is-referenced-by-count":0,"title":["Enzyme Activation of Triggerable Polymeric Lysosome Targeting Chimeras"],"prefix":"10.64898","author":[{"given":"Badal","family":"Singh","sequence":"first","affiliation":[{"name":"Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts 01003"},{"name":"Center for Bioactive Delivery, Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priyanath","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts 01003"},{"name":"Center for Bioactive Delivery, Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aniket","family":"Majee","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts 01003"},{"name":"Center for Bioactive Delivery, Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Tajdi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts 01003"},{"name":"Center for Bioactive Delivery, Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anirudh","family":"Deverajan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts 01003"},{"name":"Center for Bioactive Delivery, Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Lomeli","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts 01003"},{"name":"Center for Bioactive Delivery, Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia","family":"Talluri","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts 01003"},{"name":"Center for Bioactive Delivery, Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranit","family":"Dutta","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts 01003"},{"name":"Center for Bioactive Delivery, Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003"},{"name":"Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Thayumanavan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts 01003"},{"name":"Center for Bioactive Delivery, Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003"},{"name":"Department of Biomedical Engineering, University of Massachusetts Amherst, Amherst, Massachusetts 01003"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"issue":"8","key":"2026091012250811000_2026.09.03.749226v1.1","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1016\/j.chembiol.2020.07.020","article-title":"PROTACs: An Emerging Therapeutic Modality in Precision Medicine","volume":"27","year":"2020","journal-title":"Cell Chem. 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