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Therapeutic resistance in cancer cells is mediated by significant genomic instability due to their oncogenic transformation and evolutionary pressures inside the tumor microenvironment (TME). However, these cellular and molecular adaptations can result in a significant increase in the baseline endoplasmic reticulum (ER) stress in TME\u2010resident cells. This can be taken advantage of as a therapeutic strategy by using the metal chelate copper diethyldithiocarbamate (CuET), a potent inhibitor of the p97\u2010UFD1\u2010NPL4 protein complex to induce cytotoxicity and exacerbate ER stress\u00a0in cancer cells. Here, CuET is combined with the anti\u2010inflammatory drug 6\u2010bromo\u2010indirubin\u20103\u2032\u2010oxime (BIO), a potent GSK3 inhibitor, to modulate the aberrant inflammatory response\u00a0inside the TME. However, both CuET and BIO are highly hydrophobic and exhibit poor bioavailability, requiring the development of an appropriate carrier. Herein, it is demonstrated that CuET and BIO can be efficiently loaded into liposomes that are stabilized by poly(vinylpyrrolidone). The liposome\u2010loaded drug combination resulted in a significant decrease of 47% and 76% in the tumor burden of syngeneic B16F10 and YUMM1.7 mouse models, respectively, without any major acute toxicity.<\/jats:p>","DOI":"10.1002\/smll.202409012","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T08:53:55Z","timestamp":1746176035000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Liposome\u2010Polymer Nanoparticles Loaded with Copper Diethyldithiocarbamate and 6\u2010Bromo\u2010Indirubin\u20103\u2032\u2010Oxime Enable the Treatment of Refractive Melanoma"],"prefix":"10.1002","volume":"21","author":[{"given":"Radu A.","family":"Paun","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Faculty of Medicine and Health Sciences McGill University  3775 University Street Montreal QC H3A 2B6 Canada"},{"name":"Research Institute of the McGill University 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