Exploiting mechanistic insights to improve the delivery of nanomaterials and extracellular vesicles to tumors.

The main current challenges in oncology therapy are (1) improving the targeting of chemotherapeutics to tumors and (2) developing alternative treatments for metastatic tumors. Nanomedicine can provide an answer to these problems; however, the delivery of sufficient therapeutic nanoparticles (NPs) to tumors remains a huge challenge in nanomaterial-based treatments. Extracellular vesicles (EVs) are key participants in intercellular communication processes that can be combined with nanomaterials to enhance their targeting. Available evidence indicates that Caveolin-1 (CAV1) when expressed in cancer cells modulates the protein cargos of EVs such as to enhance migration, invasion and metastasis of recipient cancer cells. Furthermore, these effects are favored by CAV1 phosphorylation at tyrosine 14. Considering this role of CAV1 and its phosphorylation on Y14 in the EV cargo sorting of certain cell adhesion proteins, such as β3 and β5 integrins important for EV tropism, we evaluated the biodistribution of EVs loaded with gold nanoparticles from B16F10 cells expressing wild-type (CAV1) phosphomimetic (CAV1/Y14E) and phospho-null (CAV1/Y14F) in a pre-clinical murine model of lung metastasis. The experiments revealed that EVs(CAV1)-AuNPs and EVs(CAV1/Y14E)-AuNPs reached more rapidly and accumulated to a greater extent in small metastatic lung tumors compared to control EVs or EVs(CAV1/Y14F). As expected, a higher accumulation of gold in vitro in B16F10 cells, as well as in vivo in small metastatic lung nodules was detected when EVs(CAV1) or EVs(CAV1/Y14E) were used as vehicles for the AuNPs. Thus, CAV1 expression enhances the accumulation and targeting of AuNP-loaded melanoma cell-derived EVs to small metastatic lung tumors formed by their parental B16F10 cells. Importantly, the enhanced targeting capacity of EVs(CAV1)-AuNPs was found to be dependent on CAV1 phosphorylation at tyrosine 14.