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However, previously reported synthetic ion transporters showed limited value, as promiscuous ionic disruption caused toxicity to both healthy cells and cancer cells indiscriminately. Here we report a simple yet efficient synthetic K+ transporter that takes advantage of the endogenous subcellular pH gradient and membrane potential to site-selectively mediate K+\/H+ transport on the mitochondrial and lysosomal membranes in living cells. Consequent mitochondrial and lysosomal damages enhanced cytotoxicity to chemo-resistant ovarian cancer stem cells (CSCs) via apoptosis induction and autophagy suppression with remarkable selectivity (up to 47-fold). The eradication of CSCs blunted tumor formation in mice. We believe this strategy can be exploited in the structural design and applications of next-generation synthetic cation transporters for the treatment of cancer and other diseases related to dysfunctional K+ channels.<\/jats:p>","DOI":"10.1021\/jacs.0c02134","type":"journal-article","created":{"date-parts":[[2020,5,22]],"date-time":"2020-05-22T14:30:15Z","timestamp":1590157815000},"page":"10769-10779","source":"Crossref","is-referenced-by-count":56,"title":["Mediating\nK+\/H+ Transport on\nOrganelle Membranes to Selectively Eradicate Cancer Stem Cells with\na Small Molecule"],"prefix":"10.1021","volume":"142","author":[{"given":"Fang-Fang","family":"Shen","sequence":"first","affiliation":[{"name":"The University of Hong Kong , , Pokfulam Road , ,","place":["Hong Kong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng-Yao","family":"Dai","sequence":"additional","affiliation":[{"name":"The University of Hong Kong , , Pokfulam Road , ,","place":["Hong Kong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nai-Kei","family":"Wong","sequence":"additional","affiliation":[{"name":"The University of Hong Kong , , Pokfulam Road , ,","place":["Hong Kong, China"]},{"name":"Shenzhen Third People\u2019s Hospital, The Second Hospital Affiliated to Southern University of Science and Technology , , ,","place":["Shenzhen, China, 518112"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Deng","sequence":"additional","affiliation":[{"name":"The University of Hong Kong , , Pokfulam Road , ,","place":["Hong Kong, China"]},{"name":"The University of Hong Kong , , Pokfulam Road , ,","place":["Hong Kong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0676-6475","authenticated-orcid":true,"given":"Alice Sze-Tsai","family":"Wong","sequence":"additional","affiliation":[{"name":"The University of Hong Kong , , Pokfulam Road , ,","place":["Hong Kong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1726-9335","authenticated-orcid":true,"given":"Dan","family":"Yang","sequence":"additional","affiliation":[{"name":"The University of Hong Kong , , Pokfulam Road , ,","place":["Hong Kong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,5,22]]},"reference":[{"key":"2026081721070584200_cit1","doi-asserted-by":"publisher","first-page":"1461","DOI":"10.1126\/science.1113666","article-title":"Principles\nof Selective Ion Transport in Channels and\nPumps","volume":"310","author":"Gouaux","year":"2005","journal-title":"Science"},{"key":"2026081721070584200_cit2","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/s41586-019-1018-5","article-title":"Small-molecule ion channels increase\nhost defences in cystic fibrosis airway epithelia","volume":"567","author":"Muraglia","year":"2019","journal-title":"Nature"},{"key":"2026081721070584200_cit3","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1126\/science.aah3862","article-title":"Restored iron transport by a small\nmolecule promotes absorption and hemoglobinization in animals","volume":"356","author":"Grillo","year":"2017","journal-title":"Science"},{"key":"2026081721070584200_cit4","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1038\/nchem.2384","article-title":"Efficient, non-toxic anion transport\nby synthetic carriers in cells and epithelia","volume":"8","author":"Li","year":"2016","journal-title":"Nat. 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