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Here, we present biotinylated PEGylated bilirubin nanobubbles encapsulating perfluoropentane gas (bt\u2010PEG\u2010BR@PFP) as ROS\u2010responsive contrast agents for dual\u2010modality ultrasound (US) and magnetic resonance imaging (MRI). Upon ROS exposure, the bilirubin shell undergoes oxidative degradation, leading to nanobubble fusion and signal amplification in both US and T\n                    <jats:sub>2<\/jats:sub>\n                    *\u2010weighted MRI. In vitro, biotin\u2010mediated cellular uptake and ROS\u2010induced fusion were validated in A549 cancer cells. In vivo, intratumoral injection of bt\u2010PEG\u2010BR@PFP into dual\u2010tumor xenografts led to a &gt;3.7\u2010fold increase in US signal intensity in ROS\u2010high A549 tumors compared to ROS\u2010low DU145 tumors, which was abolished by the ROS scavenger N\u2010acetylcysteine. Following systemic administration, the nanobubbles accumulated selectively in A549 tumors through biotin\u2010mediated targeting and produced \u223c50\u2010fold higher US signal than in DU145 tumors. In contrast, the clinical agent SonoVue showed no such tumor selectivity and ROS\u2010responsive signal enhancement. MRI studies revealed a time\u2010dependent signal drop only in A549 tumors treated with bt\u2010PEG\u2010BR@PFP, consistent with ROS\u2010mediated nanobubble fusion. These results highlight bt\u2010PEG\u2010BR@PFP as a promising and clinically translatable platform for non\u2010invasive, dual\u2010modality imaging of tumor oxidative stress, with potential utility in various ROS\u2010associated pathologies.\n                  <\/jats:p>","DOI":"10.1002\/advs.202600071","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T15:02:57Z","timestamp":1778684577000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ROS\u2010Responsive Nanobubbles for Dual\u2010Enhanced Ultrasound and Magnetic Resonance Imaging of Tumor Oxidative Stress"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8792-6540","authenticated-orcid":false,"given":"Wonsik","family":"Jung","sequence":"first","affiliation":[{"name":"Department of Biological Sciences KAIST Institute for BioCentury Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of Korea"},{"name":"Center for Precision Bio\u2010Nanomedicine Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5120-4722","authenticated-orcid":false,"given":"Youngju","family":"Son","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences KAIST Institute for BioCentury Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of Korea"},{"name":"Center for Precision Bio\u2010Nanomedicine Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Yun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine Asan Medical Center University of Ulsan College of Medicine  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youngeun","family":"Jeon","sequence":"additional","affiliation":[{"name":"Department of Bio and Brain Engineering Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Asaddudin","sequence":"additional","affiliation":[{"name":"Department of Bio and Brain Engineering Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1731-0668","authenticated-orcid":false,"given":"Sung\u2010Hong","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Bio and Brain Engineering Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6971-586X","authenticated-orcid":false,"given":"Sangyong","family":"Jon","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences KAIST Institute for BioCentury Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of Korea"},{"name":"Center for Precision Bio\u2010Nanomedicine Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,13]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2004.04.032"},{"key":"e_1_2_9_3_1","first-page":"794","article-title":"Production of Large Amounts of Hydrogen Peroxide by Human Tumor Cells","volume":"51","author":"Szatrowski T. 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