{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:17:52Z","timestamp":1785421072301,"version":"3.56.0"},"reference-count":66,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003093","name":"Ministry of Higher Education, Malaysia","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003093","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/05v8z6a72","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Multidrug efflux proteins, frequently overexpressed in cancer cells, reduce intracellular drug accumulation and limit chemotherapeutic efficacy. Short drug-binding peptides containing the WXXW motif have been shown to non-covalently bind multidrug resistance (MDR)-associated drugs, potentially masking structural features recognized by efflux transporters. We hypothesized that incorporating this motif into a membrane-active peptide would generate a hybrid analogue capable of reversible drug binding and enhanced cellular uptake. Methods: A melittin-derived peptide (M3) was rationally designed by introducing the WXXW motif into the flexible region adjacent to the conserved proline kink to generate a dual-functional peptide with membrane activity and reversible drug binding. Membrane activity was evaluated using liposome leakage assays, and drug-binding interactions with doxorubicin were characterized using fluorescence quenching and microscale thermophoresis (MST). Molecular dynamics simulations were performed to elucidate binding mechanisms, and functional effects were assessed using calcein AM efflux assays, confocal imaging, and cytotoxicity studies across cancer cell lines. Results: M3 retained membrane activity and exhibited moderate, reversible binding to doxorubicin, with simulations showing binding initiation at the WXXW motif and extension to tryptophan residues W12, W15, and W19, forming a multivalent aromatic interface that suggested shielding of key drug functionalities. Functionally, M3 enhanced intracellular calcein retention and increased doxorubicin accumulation, and combination treatment produced synergistic cytotoxicity in the multidrug-resistant H69AR cell line with reduced toxicity toward normal epithelial cells. Conclusions: M3 acts as a membrane-active, reversible drug-binding peptide that enhances intracellular drug accumulation, supporting its potential as a modular strategy to overcome efflux-mediated MDR.<\/jats:p>","DOI":"10.3390\/pharmaceutics18070853","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T10:12:53Z","timestamp":1784023973000},"page":"853","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Engineered Melittin Delivers a Drug-Loaded \u2018Chemo-Sting\u2019 to Overcome Efflux-Mediated Multidrug Resistance in Cancer Cells"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9139-8979","authenticated-orcid":false,"given":"Nurul Ain Mohammad","family":"Hamdi","sequence":"first","affiliation":[{"name":"Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya M.","family":"Emam","sequence":"additional","affiliation":[{"name":"Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK"},{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Bryce","sequence":"additional","affiliation":[{"name":"Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4515-755X","authenticated-orcid":false,"given":"Constantinos","family":"Demonacos","sequence":"additional","affiliation":[{"name":"Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5648-3564","authenticated-orcid":false,"given":"Jian R.","family":"Lu","sequence":"additional","affiliation":[{"name":"Biological Physics, Department of Physics and Astronomy, University of Manchester, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6266-3147","authenticated-orcid":false,"given":"Harmesh S.","family":"Aojula","sequence":"additional","affiliation":[{"name":"Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA A Cancer J. 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