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Hypoxia also promotes epithelial\u2013mesenchymal transition (EMT), leading to acceleration of tumor metastasis. Many chemotherapeutic drugs can further exacerbate hypoxia and thus promote metastasis. Therefore, relieving hypoxia is necessary for chemotherapy to inhibit both MDR and EMT. Herein, highly stable cerasomal perfluorocarbon nanodroplets with an atomic layer of polyorganosiloxane surface and pH-sensitive tumor-targeting peptide (D-vPCs-O2) were fabricated to co-deliver oxygen and therapeutic drug, doxorubicin. High-intensity focused ultrasound (HIFU) was utilized to trigger the co-release of doxorubicin and oxygen and simultaneously enhance ultrasound imaging, therefore achieving imaging-guided drug delivery. Mild-temperature HIFU (M-HIFU) not only triggered oxygen release from nanodroplets but also slightly elevated tumor temperature to accelerate tumor blood flow. The oxygen release and temperature elevation jointly relieved tumor hypoxia and alleviated MDR, which greatly enhanced the drug therapeutic efficacy as compared to clinically used doxorubicin and Doxil. Overall side effects were also largely reduced owing to the ultrastable drug loading of cerasome. The improvement of insufficient chemotherapy and the relief of tumor hypoxia corporately down-regulated TGF-\u03b21, leading to the alleviation of EMT, and therefore significantly inhibited tumor metastasis. When \u201cD-vPCs-O2 + M-HIFU\u201d was utilized as a neoadjuvant chemotherapy, nanodroplets down-regulated heat shock proteins, reducing tumor relapse after the high-temperature HIFU (H-HIFU)-mediated hyperthermia ablation. The chemo-hyperthermia therapy totally eradicated tumors without any relapse or metastasis, providing a promising way to treat the triple-negative breast cancer, which is highly malignant, easily metastatic, and lacks effective treatments.<\/jats:p>","DOI":"10.1021\/acsnano.0c07287","type":"journal-article","created":{"date-parts":[[2020,11,11]],"date-time":"2020-11-11T14:21:30Z","timestamp":1605104490000},"page":"15904-15918","source":"Crossref","is-referenced-by-count":103,"title":["High\nIntensity Focused Ultrasound-Responsive and Ultrastable\nCerasomal Perfluorocarbon Nanodroplets for Alleviating Tumor Multidrug\nResistance and Epithelial\u2013Mesenchymal Transition"],"prefix":"10.1021","volume":"14","author":[{"given":"Xiaotu","family":"Ma","sequence":"first","affiliation":[{"name":"Peking University Third Hospital , , ,","place":["Beijing, P.R. China, 100191"]},{"name":"Chinese Academy of Sciences , , ,","place":["Beijing, P.R. China, 100101"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, P.R. China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meinan","family":"Yao","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, P.R. China, 100191"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7220-9637","authenticated-orcid":true,"given":"Jiyun","family":"Shi","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Beijing, P.R. China, 100101"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoda","family":"Li","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, P.R. China, 100191"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Gao","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Beijing, P.R. China, 100101"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Luo","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Beijing, P.R. China, 100101"]},{"name":"Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory) , ,","place":["Guangzhou, P.R. China, 510005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Hou","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, P.R. China, 100191"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7299-3329","authenticated-orcid":true,"given":"Xiaolong","family":"Liang","sequence":"additional","affiliation":[{"name":"Peking University Third Hospital , , ,","place":["Beijing, P.R. China, 100191"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4166-5776","authenticated-orcid":true,"given":"Fan","family":"Wang","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Beijing, P.R. China, 100101"]},{"name":"Peking University , , ,","place":["Beijing, P.R. China, 100191"]},{"name":"Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory) , ,","place":["Guangzhou, P.R. China, 510005"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,11,11]]},"reference":[{"key":"2026081720235170700_cit1","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of Cancer:\nThe Next Generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"2026081720235170700_cit2","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1038\/nrc704","article-title":"Hypoxia\n- A Key Regulatory Factor in Tumour Growth","volume":"2","author":"Harris","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"2026081720235170700_cit3","doi-asserted-by":"publisher","first-page":"1703197","DOI":"10.1002\/adfm.201703197","article-title":"Cancer Cell Membrane-Biomimetic Oxygen Nanocarrier\nfor Breaking Hypoxia-Induced Chemoresistance","volume":"27","author":"Tian","year":"2017","journal-title":"Adv. Funct. Mater."},{"key":"2026081720235170700_cit4","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1038\/nm1469","article-title":"Tumor Metastasis:\nMechanistic Insights and Clinical Challenges","volume":"12","author":"Steeg","year":"2006","journal-title":"Nat. Med."},{"key":"2026081720235170700_cit5","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1126\/science.aaf4405","article-title":"Hypoxic Control\nof Metastasis","volume":"352","author":"Rankin","year":"2016","journal-title":"Science"},{"key":"2026081720235170700_cit6","doi-asserted-by":"publisher","first-page":"1701429","DOI":"10.1002\/adma.201701429","article-title":"Erythrocyte-Membrane-Enveloped\nPerfluorocarbon\nas Nanoscale Artificial Red Blood Cells to Relieve Tumor Hypoxia and\nEnhance Cancer Radiotherapy","volume":"29","author":"Gao","year":"2017","journal-title":"Adv. Mater."},{"key":"2026081720235170700_cit7","doi-asserted-by":"publisher","first-page":"6145","DOI":"10.1021\/acs.nanolett.6b02365","article-title":"Ultrasound\nTriggered Tumor Oxygenation with Oxygen-Shuttle Nanoperfluorocarbon\nto Overcome Hypoxia-Associated Resistance in Cancer Therapies","volume":"16","author":"Song","year":"2016","journal-title":"Nano Lett."},{"key":"2026081720235170700_cit8","doi-asserted-by":"publisher","first-page":"8785","DOI":"10.1038\/ncomms9785","article-title":"Perfluorocarbon\nNanoparticles Enhance Reactive Oxygen Levels and Tumour Growth Inhibition\nin Photodynamic Therapy","volume":"6","author":"Cheng","year":"2015","journal-title":"Nat. Commun."},{"key":"2026081720235170700_cit9","doi-asserted-by":"publisher","first-page":"2716","DOI":"10.1002\/adma.201504617","article-title":"Perfluorocarbon-Loaded\nHollow Bi2Se3 Nanoparticles for Timely Supply\nof Oxygen under\nNear-Infrared Light to Enhance the Radiotherapy of Cancer","volume":"28","author":"Song","year":"2016","journal-title":"Adv. Mater."},{"key":"2026081720235170700_cit10","doi-asserted-by":"publisher","first-page":"17670","DOI":"10.1021\/jacs.9b07591","article-title":"A Responsive\nMesoporous Silica Nanoparticle Platform for Magnetic Resonance Imaging-Guided\nHigh-Intensity Focused Ultrasound-Stimulated Cargo Delivery with Controllable\nLocation, Time, and Dose","volume":"141","author":"Cheng","year":"2019","journal-title":"J. Am. Chem. Soc."},{"key":"2026081720235170700_cit11","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.addr.2014.01.006","article-title":"Magnetic Resonance Guided High-Intensity\nFocused Ultrasound for Image-Guided Temperature-Induced Drug Delivery","volume":"72","author":"Hijnen","year":"2014","journal-title":"Adv. Drug Delivery Rev."},{"key":"2026081720235170700_cit12","doi-asserted-by":"publisher","first-page":"1280","DOI":"10.1021\/nn507482w","article-title":"Nanohybrid\nLiposomal Cerasomes with Good Physiological\nStability and Rapid Temperature Responsiveness for High Intensity\nFocused Ultrasound Triggered Local Chemotherapy of Cancer","volume":"9","author":"Liang","year":"2015","journal-title":"ACS Nano"},{"key":"2026081720235170700_cit13","doi-asserted-by":"publisher","first-page":"1804901","DOI":"10.1002\/adfm.201804901","article-title":"Covalent Organic Polymers\nBased on Fluorinated Porphyrin as Oxygen Nanoshuttles for Tumor Hypoxia\nRelief and Enhanced Photodynamic Therapy","volume":"28","author":"Tao","year":"2018","journal-title":"Adv.\nFunct. Mater."},{"key":"2026081720235170700_cit14","doi-asserted-by":"publisher","first-page":"7378","DOI":"10.1002\/adma.201402969","article-title":"A Drug-Perfluorocarbon\nNanoemulsion with an Ultrathin\nSilica Coating for the Synergistic Effect of Chemotherapy and Ablation\nby High-Intensity Focused Ultrasound","volume":"26","author":"Ma","year":"2014","journal-title":"Adv. Mater."},{"key":"2026081720235170700_cit15","doi-asserted-by":"publisher","first-page":"11622","DOI":"10.1002\/anie.201103557","article-title":"Conjugation of Porphyrin to Nanohybrid\nCerasomes for Photodynamic Diagnosis and Therapy of Cancer","volume":"50","author":"Liang","year":"2011","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026081720235170700_cit16","doi-asserted-by":"publisher","first-page":"e390","DOI":"10.1016\/S1470-2045(19)30158-5","article-title":"Changing Frameworks in Treatment Sequencing of Triple-Negative\nand HER2-Positive, Early-Stage Breast Cancers","volume":"20","author":"Pusztai","year":"2019","journal-title":"Lancet Oncol."},{"key":"2026081720235170700_cit17","doi-asserted-by":"publisher","first-page":"2014","DOI":"10.1021\/acs.bioconjchem.6b00306","article-title":"PET Imaging of Extracellular pH in\nTumors with (64)\u00adCu- and (18)\u00adF-Labeled pHLIP Peptides: A Structure-Activity\nOptimization Study","volume":"27","author":"Demoin","year":"2016","journal-title":"Bioconjugate Chem."},{"key":"2026081720235170700_cit18","doi-asserted-by":"publisher","first-page":"3218","DOI":"10.1002\/anie.200200550","article-title":"Injectable Microbubbles\nas Contrast Agents for Diagnostic Ultrasound Imaging: The Key Role\nof Perfluorochemicals","volume":"42","author":"Schutt","year":"2003","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026081720235170700_cit19","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.jconrel.2018.02.026","article-title":"Co-Delivery Nanoparticle to Overcome\nMetastasis Promoted\nby Insufficient Chemotherapy","volume":"275","author":"Zhou","year":"2018","journal-title":"J. Controlled\nRelease"},{"key":"2026081720235170700_cit20","doi-asserted-by":"publisher","first-page":"1429","DOI":"10.1172\/JCI36183","article-title":"Biomarkers for Epithelial-Mesenchymal Transitions","volume":"119","author":"Zeisberg","year":"2009","journal-title":"J. Clin. Invest."},{"key":"2026081720235170700_cit21","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1038\/s41556-018-0256-3","article-title":"Chemotherapy Elicits\nPro-Metastatic Extracellular Vesicles in Breast Cancer Models","volume":"21","author":"Keklikoglou","year":"2019","journal-title":"Nat. Cell Biol."},{"key":"2026081720235170700_cit22","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1038\/nrc1591","article-title":"High-Intensity\nFocused Ultrasound in the Treatment of Solid Tumours","volume":"5","author":"Kennedy","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"2026081720235170700_cit23","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1016\/S1470-2045(02)00818-5","article-title":"Hyperthermia in\nCombined Treatment of Cancer","volume":"3","author":"Wust","year":"2002","journal-title":"Lancet Oncol."},{"key":"2026081720235170700_cit24","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1038\/nrclinonc.2015.63","article-title":"Surgical Issues in\nPatients with Breast Cancer Receiving\nNeoadjuvant Chemotherapy","volume":"12","author":"King","year":"2015","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"2026081720235170700_cit25","doi-asserted-by":"publisher","first-page":"902","DOI":"10.1038\/s41467-017-01050-0","article-title":"Hollow MnO2 as a Tumor-Microenvironment-Responsive\nBiodegradable Nano-Platform for Combination Therapy Favoring Antitumor\nImmune Responses","volume":"8","author":"Yang","year":"2017","journal-title":"Nat. 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