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.

Automated summary

Researchers have developed a biomimetic drug delivery system based on lemon-derived extracellular vesicles (EVs) nanodrugs, which effectively overcomes multidrug resistance in cancer. By modifying functional heparin-cRGD (HR) onto the surface of EVs and loading them with doxorubicin (DOX), the researchers created HRED that can enter DOX-resistant cancer cells through various endocytosis pathways and exhibit excellent cellular uptake capacity. The HRED's diverse endocytosis capability dissipates intracellular energy and reduces ATP production, leading to a significant reduction in drug efflux. The authors believe that this strategy provides a new approach for designing drug delivery systems to overcome multidrug resistance in cancer.