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Turn\u2010on, ligand\u2010directed fluorescent probes have advanced the study of these receptors by enabling low\u2010background imaging and the sensing of interactions with binding partners. However, their broader utility is hindered by the difficulty of tuning specificity, binding affinity, and emission properties for each new target. Here, we introduce a highly modular molecular beacon (MB)\u2010based platform that overcomes these limitations. Building on the spatial proximity of many cell\u2010surface receptors and the conformational switching of MBs, we designed multivalent, ligand\u2010appended hairpin probes that strongly engage these receptors while undergoing stem opening and fluorescence activation at the cell surface. This design, together with the structural programmability of these single\u2010stranded DNA constructs, enables tuning of emission wavelength, receptor selectivity, and binding strength through simple exchange of fluorophores and ligands, and modulation of valency. For rapidly endocytosed receptors, we further demonstrate an alternative long\u2010stem MB design that exploits intracellular probe cleavage to trigger fluorescence. By applying these MBs to image distinct receptors, distinguish cellular states, and detect receptor\u2013inhibitor interactions under wash\u2010free conditions, we demonstrate a versatile and generalizable strategy for probing cell\u2010surface receptors in living cells.<\/jats:p>","DOI":"10.1002\/anie.3191334","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T15:52:17Z","timestamp":1790869937000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ligand\u2010Directed Molecular Beacons as Turn\u2010On Fluorescent Probes for Sensing Cell\u2010Surface Receptor\u2010Ligand Interactions"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-5643-5019","authenticated-orcid":false,"given":"Noa","family":"Oppenheimer\u2010Low","sequence":"first","affiliation":[{"name":"Department of Chemical and Structural Biology Weizmann Institute of Science  Rehovot 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