A Biomimetic Drug Delivery System by Integrating Grapefruit Extracellular Vesicles and Doxorubicin-Loaded Heparin-Based Nanoparticles for Glioma Therapy.

Existing nanoparticle-mediated drug delivery systems for glioma systemic chemotherapy remain a great challenge due to poor delivery efficiency resulting from the blood brain barrier/blood-(brain tumor) barrier (BBB/BBTB) and insufficient tumor penetration. Here, we demonstrate a distinct design by patching doxorubicin-loaded heparin-based nanoparticles (DNs) onto the surface of natural grapefruit extracellular vesicles (EVs), to fabricate biomimetic EV-DNs, achieving efficient drug delivery and thus significantly enhancing antiglioma efficacy. The patching strategy allows the unprecedented 4-fold drug loading capacity compared to traditional encapsulation for EVs. The biomimetic EV-DNs are enabled to bypass BBB/BBTB and penetrate into glioma tissues by receptor-mediated transcytosis and membrane fusion, greatly promoting cellular internalization and antiproliferation ability as well as extending circulation time. We demonstrate that a high-abundance accumulation of EV-DNs can be detected at glioma tissues, enabling the maximal brain tumor uptake of EV-DNs and great antiglioma efficacy in vivo.

Self-anti-angiogenesis nanoparticles enhance anti-metastatic-tumor efficacy of chemotherapeutics.

Beyond traditional endothelium-dependent vessel (EDV), vascular mimicry (VM) is another critical tumor angiogenesis that further forms in many malignant metastatic tumors. However, the existing anti-angiogenesis combined chemotherapeutics strategies are only efficient for the treatment of EDV-based subcutaneous tumors, but remain a great challenge for the treatment of in situ malignant metastatic tumor associated with EDV and VM. Here, we demonstrate a self-assembled nanoparticle (VE-DDP-Pro) featuring self-anti-EDV and -VM capacity enables to significantly enhance the treatment efficacy of cisplatin (DDP) against the growth and metastasis of ovarian cancer. The VE-DDP-Pro is constructed by patching DDP loaded cRGD-folate-heparin nanoparticles (VE) onto the surface of protamine (Pro) nanoparticle. We demonstrated the self-anti-angiogenesis capacity of VE-DDP-Pro was attributed to VE, which could significantly inhibit the formation of EDV and VM by regulating signaling pathway of MMP-2/VEGF, AKT/mTOR/MMP-2/Laminin and AKT/mTOR/EMT, facilitating chemotherapeutics to effectively suppress the development and metastasis of ovarian cancer. Thus, combing with the chemotherapeutics effectiveness of DDP, the VE-DDP-Pro can significantly enhance treatment efficacy and prolong median survival of mice with metastatic ovarian cancer. We believe our self-assembled nanoparticles integrating the anti-EDV and anti-VM capacity provide a new preclinical sight to enhance the efficacy of chemotherapeutics for the treatment malignant metastasis tumor.