Fruit-Derived Extracellular-Vesicle-Engineered Structural Droplet Drugs for Enhanced Glioblastoma Chemotherapy

Existing solid-nanoparticle-based drug delivery systems remain a great challenge for glioblastoma chemotherapy due to their poor capacities in crossing the blood-brain barrier/blood-brain tumor barrier (BBB/BBTB). Herein, fruit-derived extracellular-vesicle (EV)-engineered structural droplet drugs (ESDDs) are demonstrated by programming the self-assembly of fruit-derived EVs at the DOX@squalene-PBS interface, greatly enhancing the antitumor efficacy against glioblastoma. The ESDDs experience a flexible delivery via deformation-amplified macropinocytosis and membrane fusion, enabling them to highly efficiently cross the BBB/BBTB and deeply penetrate glioblastoma tissues. As expected, the ESDDs exhibit approximately 2.5-fold intracellular uptake, 2.2-fold transcytosis, and fivefold membrane fusion higher than cRGD-modified EVs (REs), allowing highly efficient accumulation, deep penetration, and cellular internalization into the glioblastoma tissues, and thereby significantly extending the survival time of glioblastoma mice.