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.

Lemon-Derived Extracellular Vesicles Nanodrugs Enable to Efficiently Overcome Cancer Multidrug Resistance by Endocytosis-Triggered Energy Dissipation and Energy Production Reduction.

Multidrug resistance remains a great challenge for cancer chemotherapy. Herein, a biomimetic drug delivery system based on lemon-derived extracellular vesicles (EVs) nanodrugs (marked with heparin-cRGD-EVs-doxorubicin (HRED)) is demonstrated, achieving highly efficient overcoming cancer multidrug resistance. The HRED is fabricated by modifying functional heparin-cRGD (HR) onto the surface of EVs and then by loading with doxorubicin (DOX). The obtained HRED enable to effectively enter DOX-resistant cancer cells by caveolin-mediated endocytosis (main), macropinocytosis (secondary), and clathrin-mediated endocytosis (last), exhibiting excellent cellular uptake capacity. The diversified endocytosis capacity of HRED can efficiently dissipate intracellular energy and meanwhile trigger downstream production reduction of adenosine triphosphate (ATP), leading to a significant reduction of drug efflux. Consequently, they show excellent anti-proliferation capacities to DOX-resistant ovarian cancer, ensuring the efficiently overcoming ovarian cancer multidrug resistance in vivo. The authors believe this strategy provides a new strategy by endocytosis triggered-energy dissipation and ATP production reduction to design drug delivery system for overcoming cancer multidrug resistance.

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.