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

Abstract

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.

Plant-derived nanovesicles: Current understanding and applications for cancer therapy

“…Heparin-cRGD was attached to the surface of the vesicles loaded with Dox. This system exhibited strong anti-proliferative effects on Dox-resistant ovarian cancer cells, which overcame drug resistance both in vitro and in vivo [ 65 ].

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Endocytosis-mediated redistribution of antibiotics targets intracellular bacteria

“…34 Pinocytosis is the general process of fluid-phase uptake by a cell and can be further divided into macropinocytosis, clathrin-mediated endocytosis, caveolin-mediated endocytosis, and clathrin/caveolae independent endocytosis, based on the majority of the literature. 35 The biological and physicochemical properties of the nanoparticle can be tailored for targeted delivery or triggered release of the cargo, resulting in enhanced therapeutic efficacy.…”

Emergence of Edible Plant-Derived Nanovesicles as Functional Food Components and Nanocarriers for Therapeutics Delivery: Potentials in Human Health and Disease

“…When nanovesicles from Asparagus cochinchinensis were PEGylated, vesicles were retained in circulation for a prolonged time and accumulated more in tumor tissue without side effects. Patching of heparin-cRGD (tripeptide Arg-Gly-Asp motif) peptide conjugates onto lemon-derived nanovesicles [ 99 ] or patching of doxorubicin loaded heparin-cRGD- based nanoparticles onto the surface of grapefruit-derived nanovesicles [ 100 ] are another examples of surface modification. Since RGD motifs are recognized by αvβ3 integrins in proliferating endothelium of tumors [ 101 ], such surface modification could improve the tumor-targeting capacity of PDNVs.…”