Bioinspired engineering of fusogen and targeting moiety equipped nanovesicles.

Cell-derived small extracellular vesicles have been exploited as potent drug vehicles. However, significant challenges hamper their clinical translation, including inefficient cytosolic delivery, poor target-specificity, low yield, and inconsistency in production. Here, we report a bioinspired material, engineered fusogen and targeting moiety co-functionalized cell-derived nanovesicle (CNV) called eFT-CNV, as a drug vehicle. We show that universal eFT-CNVs can be produced by extrusion of genetically modified donor cells with high yield and consistency. We demonstrate that bioinspired eFT-CNVs can efficiently and selectively bind to targets and trigger membrane fusion, fulfilling endo-lysosomal escape and cytosolic drug delivery. We find that, compared to counterparts, eFT-CNVs significantly improve the treatment efficacy of drugs acting on cytosolic targets. We believe that our bioinspired eFT-CNVs will be promising and powerful tools for nanomedicine and precision medicine.

Statins Lower Lipid Synthesis But Promote Secretion of Cholesterol-Enriched Extracellular Vesicles and Particles.

Lipid droplets are lipid-rich cytosolic organelles that play roles in cell signaling, membrane trafficking, and many other cellular activities. Recent studies revealed that lipid droplets in cancer cells have various biological functions, such as energy production, membrane synthesis, and chemoresistance, thereby fostering cancer progression. Accordingly, the administration of antilipemic agents could improve anti-cancer treatment efficacy given hydrophobic chemotherapeutic drugs could be encapsulated into lipid droplets and then expelled to extracellular space. In this study, we investigated whether statins could promote treatment efficacy of lipid droplet-rich ovarian SKOV-3 cells and the potential influences on generation and composition of cell-derived extracellular vesicles and particles (EVP). Our studies indicate that statins can significantly lower lipid biosynthesis. Moreover, statins can inhibit proliferation, migration, and invasion of SKOV-3 cells and enhance chemosensitivity in vitro and in vivo. Furthermore, statins can lower EVP secretion but enforce the release of cholesterol-enriched EVPs, which can further lower lipid contents in parental cells. It is the first time that the influence of statins on EVP generation and EVP-lipid composition is observed. Overall, we demonstrated that statins could inhibit lipid production, expel cholesterol to extracellular space via EVPs, and improve chemosensitivity.