Modulating exosomal communication between macrophages and melanoma cancer cells via cyclodextrin-based nanosponges loaded with doxorubicin

The cellular components of the tumor microenvironment (TME) comprise cancer cells and nonmalignant cells including stromal and immune cells. Exosomes are extracellular vesicles secreted by various types of cells that play a crucial role in intercellular communications within TME. The main goal of this study was to elucidate how exosomes of macrophage cells treated with doxorubicin (DOX) and DOX-loaded cyclodextrin-based nanosponges (DOX-CDNSs), affect melanoma cancer cell proliferation. For this aim, the exosomes of the murine macrophage cell line (RAW 264.7) were isolated and characterized after treating the cells with DOX and DOX-CDNSs. The results demonstrated that DOX-CDNSs at a treatment concentration of 1 µg/mL, were nontoxic for macrophages and remarkably toxic against cancer cells. However, DOX was nontoxic for both cell types at the same treatment concentration. DOX and DOX-CDNSs remarkably declined the viability of both cell types at higher concentrations (25 and 50 µg/mL). Intriguingly, the exosomes of DOX-CD-NSs treated macrophages promoted the viability of cancer cells at the treatment concentrations of 1, 20, and 40 µg/mL. While the exosomes of DOX-treated macrophages increased cell viability of cancer cells only at the lowest concentration. In conclusion, this study suggests that utilization of CD-NSs may augment the toxicity of DOX against cancer cells, while it could direct macrophages toward secreting exosomes that favor the growth of cancer cells.