Targeting Triple-Negative Breast Cancer Metabolism Via Engineered Virus-Like Vesicle-Mediated Drug Delivery
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Despite chemotherapy’s widespread application for cancer treatment, its targeted delivery to neoplastic tissue, especially those lipophilic in nature, remains a major challenge. Leukocyte-derived small extracellular vesicles (EVs) have emerged as promising drug carriers due to their intrinsic tumor-targeting abilities and immunological inertness. To enhance the stability and drug loading capabilities of EVs, we developed a virus-like vesicle (VLV) drug delivery system comprised of engineered leukocyte-derived EVs expressing activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) capsids and its 5’ untranslated region RNA stabilizing sequence. Our objective was to assess the VLV drug delivery platform for the encapsulation and delivery of hydrophobic mitochondrial-targeting chemotherapeutic drugs to treat triple-negative breast cancer (TNBC). Comparing endogenous and ex vivo loading strategies, endogenously loaded VLVs showed enhanced drug encapsulation and sustained cytotoxicity against TNBC cells over wild-type EVs. We conclude that the current system holds significant potential for the delivery of hydrophobic drugs to treat resistant cancers.