{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T15:42:57Z","timestamp":1777045377566,"version":"3.51.4"},"reference-count":64,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,6,12]],"date-time":"2021-06-12T00:00:00Z","timestamp":1623456000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,6,12]],"date-time":"2021-06-12T00:00:00Z","timestamp":1623456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81873900"],"award-info":[{"award-number":["81873900"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Nanobiotechnol"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Ras activation is a frequent event in hepatocellular carcinoma (HCC). Combining a RAS inhibitor with traditional clinical therapeutics might be hampered by a variety of side effects, thus hindering further clinical translation. Herein, we report on integrating an IR820 nanocapsule-augmented sonodynamic therapy (SDT) with the RAS inhibitor farnesyl-thiosalicylic acid (FTS). Using cellular and tumor models, we demonstrate that combined nanocapsule-augmented SDT with FTS induces an anti-tumor effect, which not only inhibits tumor progression, and enables fluorescence imaging. To dissect the mechanism of a combined tumoricidal therapeutic strategy, we investigated the scRNA-seq transcriptional profiles of an HCC xenograft following treatment.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Integrative single-cell analysis identified several clusters that defined many corresponding differentially expressed genes, which provided a global view of cellular heterogeneity in HCC after combined SDT\/FTS treatment. We conclude that the combination treatment suppressed HCC, and did so by inhibiting endothelial cells and a modulated immunity. Moreover, hepatic stellate secretes hepatocyte growth factor, which plays a key role in treating SDT combined FTS. By contrast, enrichment analysis estimated the functional roles of differentially expressed genes. The Gene Ontology terms \u201ccadherin binding\u201d and \u201ccell adhesion molecule binding\u201d and KEGG pathway \u201cpathway in cancer\u201d were significantly enriched by differentially expressed genes after combined SDT\/FTS therapy.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Thus, some undefined mechanisms were revealed by scRNA-seq analysis. This report provides a novel proof-of-concept for combinatorial HCC-targeted therapeutics that is based on a non-invasive anti-tumor therapeutic strategy and a RAS inhibitor.<\/jats:p>\n                \n              <\/jats:sec>","DOI":"10.1186\/s12951-021-00923-3","type":"journal-article","created":{"date-parts":[[2021,6,12]],"date-time":"2021-06-12T13:02:53Z","timestamp":1623502973000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Single-cell RNA sequencing reveals the mechanism of sonodynamic therapy combined with a RAS inhibitor in the setting of hepatocellular carcinoma"],"prefix":"10.1186","volume":"19","author":[{"given":"Bolin","family":"Wu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanchi","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiayin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haitao","family":"Shang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Dong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xitian","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongxu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yichi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunyue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Jing","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6571-9855","authenticated-orcid":false,"given":"Wen","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,6,12]]},"reference":[{"issue":"15","key":"923_CR1","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1056\/NEJMra1713263","volume":"380","author":"A Villanueva","year":"2019","unstructured":"Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019;380(15):1450\u201362.","journal-title":"N Engl J Med"},{"issue":"3","key":"923_CR2","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1007\/s11912-010-0094-3","volume":"12","author":"B Rampone","year":"2010","unstructured":"Rampone B, Schiavone B, Confuorto G. Current management of hepatocellular cancer. Curr Oncol Rep. 2010;12(3):186\u201392.","journal-title":"Curr Oncol Rep"},{"issue":"5","key":"923_CR3","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1136\/gutjnl-2013-306627","volume":"63","author":"J Bruix","year":"2014","unstructured":"Bruix J, Gores GJ, Mazzaferro V. Hepatocellular carcinoma: clinical frontiers and perspectives. Gut. 2014;63(5):844\u201355.","journal-title":"Gut"},{"issue":"4","key":"923_CR4","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1016\/j.mcna.2009.03.004","volume":"93","author":"M Mendizabal","year":"2009","unstructured":"Mendizabal M, Reddy KR. Current management of hepatocellular carcinoma. Med Clin N Am. 2009;93(4):885\u2013900.","journal-title":"Med Clin N Am"},{"issue":"1","key":"923_CR5","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.ijrobp.2012.08.043","volume":"87","author":"J Klein","year":"2013","unstructured":"Klein J, Dawson LA. Hepatocellular carcinoma radiation therapy: review of evidence and future opportunities. Int J Radiat Oncol Biol Phys. 2013;87(1):22\u201332.","journal-title":"Int J Radiat Oncol Biol Phys"},{"issue":"5","key":"923_CR6","doi-asserted-by":"publisher","first-page":"1426","DOI":"10.7150\/thno.31683","volume":"9","author":"Q Wang","year":"2019","unstructured":"Wang Q, Zhang P, Li Z, Feng X, Lv C, Zhang H, et al. Evaluation of polymer nanoformulations in hepatoma therapy by established rodent models. Theranostics. 2019;9(5):1426\u201352.","journal-title":"Theranostics"},{"key":"923_CR7","doi-asserted-by":"publisher","first-page":"100800","DOI":"10.1016\/j.nantod.2019.100800","volume":"29","author":"J Ding","year":"2019","unstructured":"Ding J, Chen J, Gao L, Jiang Z, Zhang Y, Li M, et al. Engineered nanomedicines with enhanced tumor penetration. Nano Today. 2019;29:100800.","journal-title":"Nano Today"},{"issue":"5","key":"923_CR8","doi-asserted-by":"publisher","first-page":"1178","DOI":"10.1016\/j.cclet.2019.12.001","volume":"31","author":"P Zheng","year":"2020","unstructured":"Zheng P, Liu Y, Chen J, Xu W, Li G, Ding J. Targeted pH-responsive polyion complex micelle for controlled intracellular drug delivery. Chin Chem Lett. 2020;31(5):1178\u201382.","journal-title":"Chin Chem Lett"},{"issue":"2","key":"923_CR9","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1016\/j.bioactmat.2020.08.016","volume":"6","author":"D Zhao","year":"2021","unstructured":"Zhao D, Zhu T, Li J, Cui L, Zhang Z, Zhuang X, et al. Poly(lactic-co-glycolic acid)-based composite bone-substitute materials. Bioact Mater. 2021;6(2):346\u201360.","journal-title":"Bioact Mater"},{"issue":"4","key":"923_CR10","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1016\/j.scib.2020.07.013","volume":"66","author":"X Feng","year":"2021","unstructured":"Feng X, Xu W, Liu J, Li D, Li G, Ding J, et al. Polypeptide nanoformulation-induced immunogenic cell death and remission of immunosuppression for enhanced chemoimmunotherapy. Sci Bull. 2021;66(4):362\u201373.","journal-title":"Sci Bull"},{"issue":"4","key":"923_CR11","doi-asserted-by":"publisher","first-page":"261","DOI":"10.2217\/nnm-2021-0019","volume":"16","author":"L Wei","year":"2021","unstructured":"Wei L, Chen J, Ding J. Sequentially stimuli-responsive anticancer nanomedicines. Nanomedicine (Lond). 2021;16(4):261\u20134.","journal-title":"Nanomedicine (Lond)"},{"issue":"4","key":"923_CR12","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.1053\/j.gastro.2006.01.006","volume":"130","author":"DF Calvisi","year":"2006","unstructured":"Calvisi DF, Ladu S, Gorden A, Farina M, Conner EA, Lee JS, et al. Ubiquitous activation of Ras and Jak\/Stat pathways in human HCC. Gastroenterology. 2006;130(4):1117\u201328.","journal-title":"Gastroenterology"},{"key":"923_CR13","doi-asserted-by":"crossref","unstructured":"Song W, Zheng C, Liu M, Xu Y, Qian Y, Zhang Z, et al. TRERNA1 upregulation mediated by HBx promotes sorafenib resistance and cell proliferation in HCC via targeting NRAS by sponging miR-22\u20133p. Mol Ther. 2021.","DOI":"10.1016\/j.ymthe.2021.04.011"},{"key":"923_CR14","doi-asserted-by":"publisher","first-page":"659676","DOI":"10.3389\/fonc.2021.659676","volume":"11","author":"J Hu","year":"2021","unstructured":"Hu J, Cai D, Zhao Z, Zhong GC, Gong J. Suppression of heterogeneous nuclear ribonucleoprotein C inhibit hepatocellular carcinoma proliferation, migration, and invasion via Ras\/MAPK signaling pathway. Front Oncol. 2021;11:659676.","journal-title":"Front Oncol"},{"issue":"38","key":"923_CR15","doi-asserted-by":"publisher","first-page":"22263","DOI":"10.1074\/jbc.270.38.22263","volume":"270","author":"M Marom","year":"1995","unstructured":"Marom M, Haklai R, Ben-Baruch G, Marciano D, Egozi Y, Kloog Y. Selective inhibition of Ras-dependent cell growth by farnesylthiosalisylic acid. J Biol Chem. 1995;270(38):22263\u201370.","journal-title":"J Biol Chem"},{"issue":"10","key":"923_CR16","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/S1357-4310(00)01789-5","volume":"6","author":"Y Kloog","year":"2000","unstructured":"Kloog Y, Cox AD. RAS inhibitors: potential for cancer therapeutics. Mol Med Today. 2000;6(10):398\u2013402.","journal-title":"Mol Med Today"},{"issue":"3","key":"923_CR17","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1111\/j.1349-7006.1989.tb02295.x","volume":"80","author":"N Yumita","year":"1989","unstructured":"Yumita N, Nishigaki R, Umemura K, Umemura S. Hematoporphyrin as a sensitizer of cell-damaging effect of ultrasound. Jpn J Cancer Res: Gann. 1989;80(3):219\u201322.","journal-title":"Jpn J Cancer Res: Gann"},{"issue":"52","key":"923_CR18","doi-asserted-by":"publisher","first-page":"32962","DOI":"10.1073\/pnas.2011297117","volume":"117","author":"Z Li","year":"2020","unstructured":"Li Z, Zhu L, Sun H, Shen Y, Hu D, Wu W, et al. Fluorine assembly nanocluster breaks the shackles of immunosuppression to turn the cold tumor hot. Proc Natl Acad Sci USA. 2020;117(52):32962\u20139.","journal-title":"Proc Natl Acad Sci USA"},{"issue":"7","key":"923_CR19","doi-asserted-by":"publisher","first-page":"2283","DOI":"10.1016\/j.nano.2018.06.011","volume":"14","author":"X Yang","year":"2018","unstructured":"Yang X, Li H, Qian C, Guo Y, Li C, Gao F, et al. Near-infrared light-activated IR780-loaded liposomes for anti-tumor angiogenesis and Photothermal therapy. Nanomed Nanotechnol Biol Med. 2018;14(7):2283\u201394.","journal-title":"Nanomed Nanotechnol Biol Med"},{"issue":"20","key":"923_CR20","doi-asserted-by":"publisher","first-page":"eaaz9240","DOI":"10.1126\/sciadv.aaz9240","volume":"6","author":"Z Li","year":"2020","unstructured":"Li Z, Wang Y, Shen Y, Qian C, Oupicky D, Sun M. Targeting pulmonary tumor microenvironment with CXCR4-inhibiting nanocomplex to enhance anti-PD-L1 immunotherapy. Sci Adv. 2020;6(20):eaaz9240.","journal-title":"Sci Adv"},{"issue":"12","key":"923_CR21","doi-asserted-by":"publisher","first-page":"2100","DOI":"10.1016\/j.ymthe.2019.08.008","volume":"27","author":"Z Li","year":"2019","unstructured":"Li Z, Chen G, Ding L, Wang Y, Zhu C, Wang K, et al. Increased survival by pulmonary treatment of established lung metastases with dual STAT3\/CXCR4 inhibition by siRNA nanoemulsions. Mol Ther. 2019;27(12):2100\u201310.","journal-title":"Mol Ther"},{"key":"923_CR22","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.jconrel.2018.02.036","volume":"292","author":"H Li","year":"2018","unstructured":"Li H, Yang X, Gao F, Qian C, Li C, Oupicky D, et al. Bioreduction-ruptured nanogel for switch on\/off release of Bcl2 siRNA in breast tumor therapy. J Control Release. 2018;292:78\u201390.","journal-title":"J Control Release"},{"issue":"5","key":"923_CR23","doi-asserted-by":"publisher","first-page":"1700978","DOI":"10.1002\/adhm.201700978","volume":"7","author":"G Chen","year":"2018","unstructured":"Chen G, Wang K, Wang Y, Wu P, Sun M, Oupicky D. Fluorination enhances serum stability of bioreducible poly(amido amine) polyplexes and enables efficient intravenous siRNA delivery. Adv Healthc Mater. 2018;7(5):1700978.","journal-title":"Adv Healthc Mater"},{"issue":"8","key":"923_CR24","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/S1470-2045(04)01529-3","volume":"5","author":"SB Brown","year":"2004","unstructured":"Brown SB, Brown EA, Walker I. The present and future role of photodynamic therapy in cancer treatment. Lancet Oncol. 2004;5(8):497\u2013508.","journal-title":"Lancet Oncol"},{"issue":"4","key":"923_CR25","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/S1572-1000(05)00007-4","volume":"1","author":"AP Castano","year":"2004","unstructured":"Castano AP, Demidova TN, Hamblin MR. Mechanisms in photodynamic therapy: part one-photosensitizers, photochemistry and cellular localization. Photodiagn Photodyn Ther. 2004;1(4):279\u201393.","journal-title":"Photodiagn Photodyn Ther"},{"issue":"6","key":"923_CR26","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/j.ultsonch.2004.03.004","volume":"11","author":"I Rosenthal","year":"2004","unstructured":"Rosenthal I, Sostaric JZ, Riesz P. Sonodynamic therapy\u2014a review of the synergistic effects of drugs and ultrasound. Ultrason Sonochem. 2004;11(6):349\u201363.","journal-title":"Ultrason Sonochem"},{"key":"923_CR27","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1007\/978-3-319-22536-4_22","volume":"880","author":"AP McHale","year":"2016","unstructured":"McHale AP, Callan JF, Nomikou N, Fowley C, Callan B. Sonodynamic therapy: concept, mechanism and application to cancer treatment. Adv Exp Med Biol. 2016;880:429\u201350.","journal-title":"Adv Exp Med Biol"},{"issue":"7","key":"923_CR28","first-page":"2425","volume":"31","author":"H Shibaguchi","year":"2011","unstructured":"Shibaguchi H, Tsuru H, Kuroki M, Kuroki M. Sonodynamic cancer therapy: a non-invasive and repeatable approach using low-intensity ultrasound with a sonosensitizer. Anticancer Res. 2011;31(7):2425\u20139.","journal-title":"Anticancer Res"},{"issue":"4","key":"923_CR29","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.ultras.2008.02.003","volume":"48","author":"K Tachibana","year":"2008","unstructured":"Tachibana K, Feril LB Jr, Ikeda-Dantsuji Y. Sonodynamic therapy. Ultrasonics. 2008;48(4):253\u20139.","journal-title":"Ultrasonics"},{"issue":"6","key":"923_CR30","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1007\/s00280-010-1264-6","volume":"66","author":"N Yumita","year":"2010","unstructured":"Yumita N, Okudaira K, Momose Y, Umemura S. Sonodynamically induced apoptosis and active oxygen generation by gallium-porphyrin complex, ATX-70. Cancer Chemother Pharmacol. 2010;66(6):1071\u20138.","journal-title":"Cancer Chemother Pharmacol"},{"issue":"9","key":"923_CR31","doi-asserted-by":"publisher","first-page":"880","DOI":"10.7150\/thno.3899","volume":"2","author":"N Yumita","year":"2012","unstructured":"Yumita N, Iwase Y, Nishi K, Komatsu H, Takeda K, Onodera K, et al. Involvement of reactive oxygen species in sonodynamically induced apoptosis using a novel porphyrin derivative. Theranostics. 2012;2(9):880\u20138.","journal-title":"Theranostics"},{"key":"923_CR32","doi-asserted-by":"publisher","first-page":"678444","DOI":"10.3389\/fmolb.2021.678444","volume":"8","author":"B Wu","year":"2021","unstructured":"Wu B, Shang H, Liu J, Liang X, Yuan Y, Chen Y, et al. Quantitative proteomics analysis of FFPE tumor samples reveals the influences of NET-1 siRNA nanoparticles and sonodynamic therapy on tetraspanin protein involved in hcC. Front Mol Biosci. 2021;8:678444.","journal-title":"Front Mol Biosci"},{"key":"923_CR33","doi-asserted-by":"publisher","first-page":"3953","DOI":"10.2147\/IJN.S244743","volume":"15","author":"XZ Zhao","year":"2020","unstructured":"Zhao XZ, Zhang W, Cao Y, Huang SS, Li YZ, Guo D, et al. A cleverly designed novel lipid nanosystem: targeted retention, controlled visual drug release, and cascade amplification therapy for mammary carcinoma in vitro. Int J Nanomed. 2020;15:3953\u201364.","journal-title":"Int J Nanomed"},{"key":"923_CR34","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1097\/CAD.0000000000000985","volume":"32","author":"Y Yuan","year":"2020","unstructured":"Yuan Y, Li E, Zhao J, Wu B, Na Z, Cheng W, et al. Highly penetrating nanobubble polymer enhances LINC00511-siRNA delivery for improving the chemosensitivity of triple-negative breast cancer. Anticancer Drugs. 2020;32:178\u201388.","journal-title":"Anticancer Drugs"},{"key":"923_CR35","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.jconrel.2020.06.008","volume":"326","author":"SM Chowdhury","year":"2020","unstructured":"Chowdhury SM, Abou-Elkacem L, Lee T, Dahl J, Lutz AM. Ultrasound and microbubble mediated therapeutic delivery: Underlying mechanisms and future outlook. J Control Release . 2020;326:75\u201390.","journal-title":"J Control Release"},{"key":"923_CR36","doi-asserted-by":"publisher","first-page":"9713","DOI":"10.1096\/fj.202000481R","volume":"34","author":"B Wu","year":"2020","unstructured":"Wu B, Yuan Y, Han X, Wang Q, Shang H, Liang X, et al. Structure of LINC00511-siRNA-conjugated nanobubbles and improvement of cisplatin sensitivity on triple negative breast cancer. FASEB J. 2020;34:9713\u201326.","journal-title":"FASEB J"},{"issue":"12","key":"923_CR37","doi-asserted-by":"publisher","first-page":"14129","DOI":"10.1096\/fj.201900716RR","volume":"33","author":"B Wu","year":"2019","unstructured":"Wu B, Shang H, Liang X, Sun Y, Jing H, Han X, et al. Preparation of novel targeting nanobubbles conjugated with small interfering RNA for concurrent molecular imaging and gene therapy in vivo. FASEB J. 2019;33(12):14129\u201336.","journal-title":"FASEB J"},{"issue":"1","key":"923_CR38","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1080\/10717544.2019.1667450","volume":"26","author":"H Shang","year":"2019","unstructured":"Shang H, Wu B, Liang X, Sun Y, Han X, Zhang L, et al. Evaluation of therapeutic effect of targeting nanobubbles conjugated with NET-1 siRNA by shear wave elastography: an in vivo study of hepatocellular carcinoma bearing mice model. Drug Deliv. 2019;26(1):944\u201351.","journal-title":"Drug Deliv"},{"issue":"10","key":"923_CR39","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1038\/s41577-018-0050-2","volume":"18","author":"L Adlung","year":"2018","unstructured":"Adlung L, Amit I. From the Human Cell Atlas to dynamic immune maps in human disease. Nat Rev Immunol. 2018;18(10):597\u20138.","journal-title":"Nat Rev Immunol"},{"issue":"13","key":"923_CR40","doi-asserted-by":"publisher","first-page":"2000224","DOI":"10.1002\/advs.202000224","volume":"7","author":"B Zheng","year":"2020","unstructured":"Zheng B, Wang D, Qiu X, Luo G, Wu T, Yang S, et al. Trajectory and functional analysis of PD-1(high) CD4(+)CD8(+) T cells in hepatocellular carcinoma by single-cell cytometry and transcriptome sequencing. Adv Sci. 2020;7(13):2000224.","journal-title":"Adv Sci"},{"issue":"6359","key":"923_CR41","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1126\/science.aan6828","volume":"358","author":"MJT Stubbington","year":"2017","unstructured":"Stubbington MJT, Rozenblatt-Rosen O, Regev A, Teichmann SA. Single-cell transcriptomics to explore the immune system in health and disease. Science. 2017;358(6359):58\u201363.","journal-title":"Science"},{"key":"923_CR42","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1038\/s41422-020-00412-6","volume":"31","author":"S Ma","year":"2020","unstructured":"Ma S, Sun S, Li J, Fan Y, Qu J, Sun L, et al. Single-cell transcriptomic atlas of primate cardiopulmonary aging. Cell Res. 2020;31:415\u201332.","journal-title":"Cell Res"},{"issue":"1","key":"923_CR43","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1152\/physrev.00013.2006","volume":"87","author":"G Kroemer","year":"2007","unstructured":"Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev. 2007;87(1):99\u2013163.","journal-title":"Physiol Rev"},{"issue":"1","key":"923_CR44","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1186\/s12951-021-00804-9","volume":"19","author":"Y Zhang","year":"2021","unstructured":"Zhang Y, Khan AR, Yang X, Shi Y, Zhao X, Zhai G. A sonosensitiser-based polymeric nanoplatform for chemo-sonodynamic combination therapy of lung cancer. J Nanobiotechnol. 2021;19(1):57.","journal-title":"J Nanobiotechnol"},{"key":"923_CR45","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.ultsonch.2014.06.016","volume":"22","author":"X Sun","year":"2015","unstructured":"Sun X, Xu H, Shen J, Guo S, Shi S, Dan J, et al. Real-time detection of intracellular reactive oxygen species and mitochondrial membrane potential in THP-1 macrophages during ultrasonic irradiation for optimal sonodynamic therapy. Ultrason Sonochem. 2015;22:7\u201314.","journal-title":"Ultrason Sonochem"},{"issue":"1","key":"923_CR46","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1080\/02656736.2019.1605458","volume":"36","author":"A Eranki","year":"2019","unstructured":"Eranki A, Mikhail AS, Negussie AH, Katti PS, Wood BJ, Partanen A. Tissue-mimicking thermochromic phantom for characterization of HIFU devices and applications. Int J Hyperth. 2019;36(1):518\u201329.","journal-title":"Int J Hyperth"},{"issue":"3","key":"923_CR47","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1109\/TBME.2018.2853594","volume":"66","author":"Y Zhou","year":"2019","unstructured":"Zhou Y, Yu Z, Ma Q, Guo G, Tu J, Zhang D. Noninvasive treatment-efficacy evaluation for HIFU therapy based on magneto-acousto-electrical tomography. IEEE Trans Biomed Eng. 2019;66(3):666\u201374.","journal-title":"IEEE Trans Biomed Eng"},{"issue":"1","key":"923_CR48","doi-asserted-by":"publisher","first-page":"e1583","DOI":"10.1002\/wnan.1583","volume":"12","author":"J Zhao","year":"2020","unstructured":"Zhao J, Duan L, Wang A, Fei J, Li J. Insight into the efficiency of oxygen introduced photodynamic therapy (PDT) and deep PDT against cancers with various assembled nanocarriers. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2020;12(1):e1583.","journal-title":"Wiley Interdiscip Rev Nanomed Nanobiotechnol"},{"issue":"1","key":"923_CR49","doi-asserted-by":"publisher","first-page":"8","DOI":"10.3390\/jcm9010008","volume":"9","author":"B Pucelik","year":"2019","unstructured":"Pucelik B, Arnaut LG, D\u0105browski JM. Lipophilicity of bacteriochlorin-based photosensitizers as a determinant for PDT optimization through the modulation of the inflammatory mediators. J Clin Med. 2019;9(1):8.","journal-title":"J Clin Med"},{"issue":"6","key":"923_CR50","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.3171\/2017.6.JNS162398","volume":"129","author":"S Suehiro","year":"2018","unstructured":"Suehiro S, Ohnishi T, Yamashita D, Kohno S, Inoue A, Nishikawa M, et al. Enhancement of antitumor activity by using 5-ALA-mediated sonodynamic therapy to induce apoptosis in malignant gliomas: significance of high-intensity focused ultrasound on 5-ALA-SDT in a mouse glioma model. J Neurosurg. 2018;129(6):1416\u201328.","journal-title":"J Neurosurg"},{"issue":"37","key":"923_CR51","doi-asserted-by":"publisher","first-page":"8097","DOI":"10.1002\/adma.201602012","volume":"28","author":"X Qian","year":"2016","unstructured":"Qian X, Zheng Y, Chen Y. Micro\/nanoparticle-augmented sonodynamic therapy (SDT): breaking the depth shallow of photoactivation. Adv Mater. 2016;28(37):8097\u2013129.","journal-title":"Adv Mater"},{"issue":"3","key":"923_CR52","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.1021\/jacs.6b11846","volume":"139","author":"P Huang","year":"2017","unstructured":"Huang P, Qian X, Chen Y, Yu L, Lin H, Wang L, et al. Metalloporphyrin-encapsulated biodegradable nanosystems for highly efficient magnetic resonance imaging-guided sonodynamic cancer therapy. J Am Chem Soc. 2017;139(3):1275\u201384.","journal-title":"J Am Chem Soc"},{"issue":"4","key":"923_CR53","doi-asserted-by":"publisher","first-page":"3780","DOI":"10.1021\/acsnano.8b00999","volume":"12","author":"P Zhu","year":"2018","unstructured":"Zhu P, Chen Y, Shi J. Nanoenzyme-augmented cancer sonodynamic therapy by catalytic tumor oxygenation. ACS Nano. 2018;12(4):3780\u201395.","journal-title":"ACS Nano"},{"issue":"12","key":"923_CR54","doi-asserted-by":"publisher","first-page":"12849","DOI":"10.1021\/acsnano.7b08225","volume":"11","author":"J Chen","year":"2017","unstructured":"Chen J, Luo H, Liu Y, Zhang W, Li H, Luo T, et al. Oxygen-self-produced nanoplatform for relieving hypoxia and breaking resistance to sonodynamic treatment of pancreatic cancer. ACS Nano. 2017;11(12):12849\u201362.","journal-title":"ACS Nano"},{"issue":"3","key":"923_CR55","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1177\/1534735409343693","volume":"8","author":"X Wang","year":"2009","unstructured":"Wang X, Zhang W, Xu Z, Luo Y, Mitchell D, Moss RW. Sonodynamic and photodynamic therapy in advanced breast carcinoma: a report of 3 cases. Integr Cancer Ther. 2009;8(3):283\u20137.","journal-title":"Integr Cancer Ther"},{"issue":"8","key":"923_CR56","first-page":"4589","volume":"34","author":"T Inui","year":"2014","unstructured":"Inui T, Makita K, Miura H, Matsuda A, Kuchiike D, Kubo K, et al. Case report: A breast cancer patient treated with GcMAF, sonodynamic therapy and hormone therapy. Anticancer Res. 2014;34(8):4589\u201393.","journal-title":"Anticancer Res"},{"issue":"1","key":"923_CR57","doi-asserted-by":"publisher","first-page":"2025","DOI":"10.1038\/s41467-019-09760-3","volume":"10","author":"W Yue","year":"2019","unstructured":"Yue W, Chen L, Yu L, Zhou B, Yin H, Ren W, et al. Checkpoint blockade and nanosonosensitizer-augmented noninvasive sonodynamic therapy combination reduces tumour growth and metastases in mice. Nat Commun. 2019;10(1):2025.","journal-title":"Nat Commun"},{"key":"923_CR58","doi-asserted-by":"publisher","first-page":"12499","DOI":"10.1038\/ncomms12499","volume":"7","author":"C He","year":"2016","unstructured":"He C, Duan X, Guo N, Chan C, Poon C, Weichselbaum RR, et al. Core-shell nanoscale coordination polymers combine chemotherapy and photodynamic therapy to potentiate checkpoint blockade cancer immunotherapy. Nat Commun. 2016;7:12499.","journal-title":"Nat Commun"},{"issue":"9","key":"923_CR59","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1038\/nmat4644","volume":"15","author":"R Molinaro","year":"2016","unstructured":"Molinaro R, Corbo C, Martinez JO, Taraballi F, Evangelopoulos M, Minardi S, et al. Biomimetic proteolipid vesicles for targeting inflamed tissues. Nat Mater. 2016;15(9):1037\u201346.","journal-title":"Nat Mater"},{"issue":"5","key":"923_CR60","doi-asserted-by":"publisher","first-page":"1202","DOI":"10.1016\/j.cell.2015.05.002","volume":"161","author":"EZ Macosko","year":"2015","unstructured":"Macosko EZ, Basu A, Satija R, Nemesh J, Shekhar K, Goldman M, et al. Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell. 2015;161(5):1202\u201314.","journal-title":"Cell"},{"issue":"5","key":"923_CR61","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/nbt.3192","volume":"33","author":"R Satija","year":"2015","unstructured":"Satija R, Farrell JA, Gennert D, Schier AF, Regev A. Spatial reconstruction of single-cell gene expression data. Nat Biotechnol. 2015;33(5):495\u2013502.","journal-title":"Nat Biotechnol"},{"issue":"5","key":"923_CR62","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/nbt.4096","volume":"36","author":"A Butler","year":"2018","unstructured":"Butler A, Hoffman P, Smibert P, Papalexi E, Satija R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol. 2018;36(5):411\u201320.","journal-title":"Nat Biotechnol"},{"issue":"10","key":"923_CR63","doi-asserted-by":"publisher","first-page":"4288","DOI":"10.1093\/nar\/gks042","volume":"40","author":"DJ McCarthy","year":"2012","unstructured":"McCarthy DJ, Chen Y, Smyth GK. Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation. Nucleic Acids Res. 2012;40(10):4288\u201397.","journal-title":"Nucleic Acids Res"},{"issue":"12 Suppl","key":"923_CR64","first-page":"1697","volume":"53","author":"M Kanehisa","year":"2008","unstructured":"Kanehisa M. Bioinformatics and metabolome analysis: overview. Tanpakushitsu kakusan koso Protein Nucleic Acid Enzyme. 2008;53(12 Suppl):1697.","journal-title":"Tanpakushitsu kakusan koso Protein Nucleic Acid Enzyme"}],"container-title":["Journal of Nanobiotechnology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12951-021-00923-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12951-021-00923-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12951-021-00923-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,12]],"date-time":"2021-06-12T13:06:06Z","timestamp":1623503166000},"score":1,"resource":{"primary":{"URL":"https:\/\/jnanobiotechnology.biomedcentral.com\/articles\/10.1186\/s12951-021-00923-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,12]]},"references-count":64,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["923"],"URL":"https:\/\/doi.org\/10.1186\/s12951-021-00923-3","relation":{},"ISSN":["1477-3155"],"issn-type":[{"value":"1477-3155","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,12]]},"assertion":[{"value":"9 March 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 June 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 June 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All animal studies (including the mice euthanasia procedure) were done in compliance with the regulations and guidelines of Harbin Medical University institutional animal care and conducted according to the AAALAC and the IACUC guidelines.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors have declared that no competing interest exists.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"177"}}