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Herein, we developed a mechanoresponsive drug\u2010releasing silk balloon catheter that actively releases drugs upon balloon inflation while minimizing passive drug leakage. To this end, we designed a molecular template that induces densely packed hydrophobic domains within the silk fibroin network. These domains enable strong binding and mechanoresponsive release of hydrophobic therapeutics. The biochemical effects of mechanoresponsive therapeutic release in human umbilical vein endothelial cells and foam cells support its potential for the treatment of cardiovascular plaques. Furthermore, the densely packed structure enhanced strength, toughness, and elasticity, enabling inflation up to 15 atm without bursting. Moreover, it exhibited excellent fatigue resistance and rapid elastic deflation, demonstrating physical compatibility with balloon catheter applications. In addition, a drug loss test showed that the silk balloon catheter exhibited 2,355\u2010fold lower drug loss than a commercial drug\u2010coated balloon. Finally, the silk balloon catheter achieved up to 49% dilation of the ex vivo porcine coronary artery while simultaneously exhibiting mechanoresponsive drug delivery. The proposed mechanoresponsive drug\u2010releasing silk balloon catheter enables active and localized drug delivery during angioplasty.<\/jats:p>","DOI":"10.1002\/smll.75490","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T09:11:46Z","timestamp":1788167506000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Mechanoresponsive Drug\u2010Releasing Silk Balloon Catheter for Inflation\u2010Triggered Biophysical and Biochemical Treatment of Cardiovascular Plaque"],"prefix":"10.1002","author":[{"given":"Heesu","family":"Cho","sequence":"first","affiliation":[{"name":"Department of Chemical &amp; Biomolecular Engineering College of Engineering Yonsei University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5886-8836","authenticated-orcid":false,"given":"Woojin","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Chemical &amp; Biomolecular Engineering College of Engineering Yonsei University  Seoul Republic of Korea"},{"name":"Department of Mechanical Engineering Massachusetts Institute of Technology  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung\u2010eun","family":"Heo","sequence":"additional","affiliation":[{"name":"Department of Chemical &amp; Biomolecular Engineering College of Engineering Yonsei University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoonsung","family":"Noh","sequence":"additional","affiliation":[{"name":"Department of Chemical &amp; Biomolecular Engineering College of Engineering Yonsei University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youna","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Chemical &amp; Biomolecular Engineering College of Engineering Yonsei University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2233-2028","authenticated-orcid":false,"given":"Jiyu","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Chemical &amp; Biomolecular Engineering College of Engineering Yonsei University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunseo","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Chemical &amp; Biomolecular Engineering College of Engineering Yonsei University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0264-8657","authenticated-orcid":false,"given":"Dingyun","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Chemical &amp; Biomolecular Engineering College of Engineering Yonsei University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hana","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Chemical &amp; Biomolecular Engineering College of Engineering Yonsei University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seongeun","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Chemical &amp; Biomolecular Engineering College of Engineering Yonsei University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoogyeong","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Chemical &amp; Biomolecular Engineering College of Engineering Yonsei University  Seoul Republic of Korea"},{"name":"Yonsei Center for Research Facilities Yonsei University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5191-2531","authenticated-orcid":false,"given":"Won\u2010Gun","family":"Koh","sequence":"additional","affiliation":[{"name":"Department of Chemical &amp; Biomolecular Engineering College of Engineering Yonsei University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4833-4440","authenticated-orcid":false,"given":"Sungmin","family":"Lim","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Uijeongbu St. Mary's Hospital, College of Medicine The Catholic University of Korea  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6457-1812","authenticated-orcid":false,"given":"Patrick T. 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