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. Fruit‐derived extracellular vesicle (EV)‐engineered structural droplet drugs (ESDDs) exhibit excellent stability and flexibility, enabling them to highly efficiently cross the blood–brain barrier/blood–brain tumor barrier (BBB/BBTB) and deeply penetrate into glioblastoma tissues by deformation‐amplified endocytosis and membrane fusion. As expected, the ESDDs present more efficient capacities than cRGD‐modified EVs (REs) in accumulation, deep penetration, and cellular internalization, significantly enhancing the anti‐glioblastoma efficacy.