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The agonist TGM1 interacts with TGFBR1, TGFBR2, and the co\u2010receptor CD44 through domains D1\/2, D3, and D4\/5, respectively. In contrast, the antagonist TGM6, which lacks D1\/2, but retains TGFBR2 binding through D3, targets different cells compared to TGM1. The TGM6 co\u2010receptor is unknown. Using X\u2010ray crystallography and binding studies, we show that TGM6 preferentially binds mouse TGFBR2 over human TGFBR2, and that this is essential for its antagonistic function. We identified low\u2010density lipoprotein receptor\u2010related protein 1 (LRP1) and betaglycan (TGFBR3) as co\u2010receptors for TGM6. LRP1 enhances TGM6 efficacy and is required for its antagonistic effect by promoting TGFBR2 lysosomal degradation, whereas betaglycan counteracts TGM6 in a TGFBR2\u2010dependent manner. The modular organization of TGMs enabled us to design TGM1\/6 chimeras or TGM\u2010D3 fusion with an affibody that recognizes a specific cell\u2010surface receptor, thereby altering cell\u2010type specificity and functionality. Furthermore, we developed a TGFBR2 nanobody that, on its own, has no inhibitory effect but, when fused to a receptor antibody, antagonizes TGF\u03b2 by blocking TGF\u03b2\u00a0receptor interaction in a cell\u2010selective manner. Thus, we designed programmable agents that modulate TGF\u03b2 signaling only in co\u2010receptor\u2010expressing cells.\n                  <\/jats:p>","DOI":"10.1002\/advs.75322","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T10:40:02Z","timestamp":1776681602000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Decoding the Mechanism of Action of a Parasite TGF\u03b2 Antagonist Inspires the Creation of Cell\u2010Type\u2010Specific TGF\u03b2 Modulators"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9451-8884","authenticated-orcid":false,"given":"Maarten","family":"van Dinther","sequence":"first","affiliation":[{"name":"Oncode Institute and Department of Cell and Chemical Biology Leiden University Medical Center  Leiden The 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