Interactions of Cancer-Derived Extracellular Vesicles with Glyconanotherapeutics: Effects on Vesicle Integrity

Abstract Cancer-derived extracellular vesicles (EVs) are important mediators of intercellular communication within the tumor microenvironment and contribute to tumor progression, metastasis, angiogenesis, and immune modulation. Targeting the structural integrity of cancer-associated EVs may therefore represent a complementary strategy for interfering with tumor-promoting intercellular communication. Here, we investigated how nanotherapeutic architecture and lactose functionalization affect the interaction with and integrity of EVs derived from prostate carcinoma (PC3), breast adenocarcinoma (MCF7), and glioblastoma (GamG) cells. Three generations of carbosilane dendrimers, either lactose-decorated or bearing carbohydrate-free control surface groups, were compared with linear polyoxazoline copolymers with and without lactose functionalization. Both dendrimer types induced a pronounced concentration- and generation-dependent alteration of EV integrity, whereas the linear polyoxazoline polymers produced substantially weaker effects. The susceptibility of EVs differed according to their cellular origin, with PC3-derived EVs showing the highest sensitivity to dendrimer-induced disruption. Lactose-decorated nanotherapeutics displayed affinity to galectin-3 (Gal-3), and preincubation of glycodendrimers with recombinant Gal-3 attenuated their disruptive effect, indicating that Gal-3–lactose interactions can modulate dendrimer–EV interactions. In contrast, Gal-3 preincubation of the lactose-functionalized polyoxazoline promoted EV aggregation. Cryogenic transmission electron microscopy supported DLS observations by demonstrating a concentration-dependent loss of intact EVs and the presence of disrupted membrane structures following glycodendrimer treatment. These findings demonstrate that nanomaterial architecture is a significant determinant of interactions with cancer-derived EVs and identify carbosilane dendrimers as potent modulators of EV integrity, with Gal-3-dependent interactions contributing to this effect.