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Existing sensors rely on transfection, which disrupts the intracellular microenvironment and reduces accuracy. Herein, we design a DNA biosensor with a DNA tetrahedron scaffold and a flexible ssDNA\u2010FRET element, achieving near\u2010physiological crowding sensing via a chemical\u2010driven soft\u2010matter response. Cy3\/Cy5\u2010conjugated ssDNA aggregates more tightly with increased crowding, shortening the interfluorophore distance to trigger quantifiable FRET signals, validating the structure\u2010dependent correlation between flexible soft\u2010matter agglomeration and crowding degree via simulations, PEG experiments, and FRET characterization. The tetrahedron enables transfection\u2010agent\u2010free delivery, avoiding reagent drawbacks. We achieved multivariate statistical discrimination of six cell lines based on osmotic\u2010stress\u2010induced FRET fingerprints via osmotic pressure\u2010induced crowding variations, confirming cellular crowding as a hallmark of functional heterogeneity. This work advances soft matter\u2010based biosensing and tumor biophysics.<\/jats:p>","DOI":"10.1002\/smll.75031","type":"journal-article","created":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T06:44:12Z","timestamp":1786171452000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Flexible ssDNA\u2013DNA Tetrahedron FRET Sensor for Tumor Cell Discrimination via Intracellular Crowding"],"prefix":"10.1002","author":[{"given":"Junjie","family":"Yuan","sequence":"first","affiliation":[{"name":"Key Laboratory of Sensing Technology and Biomedical Instruments of Guangdong Province School of Biomedical Engineering Shenzhen Campus of Sun Yat\u2010Sen University  Shenzhen Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yating","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Sensing Technology and Biomedical Instruments of Guangdong Province School of 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