Orange-derived extracellular vesicles nanodrugs for efficient treatment of ovarian cancer assisted by transcytosis effect.

Extracellular vesicles (EVs) have recently received much attention about the application of drug carriers due to their desirable properties such as nano-size, biocompatibility, and high stability. Herein, we demonstrate orange-derived extracellular vesicles (OEV) nanodrugs (DN@OEV) by modifying cRGD-targeted doxorubicin (DOX) nanoparticles (DN) onto the surface of OEV, enabling significantly enhancing tumor accumulation and penetration, thereby efficiently inhibiting the growth of ovarian cancer. The obtained DN@OEV enabled to inducement of greater transcytosis capability in ovarian cancer cells, which presented the average above 10-fold transcytosis effect compared with individual DN. It was found that DN@OEV could trigger receptor-mediated endocytosis to promote early endosome/recycling endosomes pathway for exocytosis and simultaneously reduce degradation in the early endosomes-late endosomes-lysosome pathway, thereby inducing the enhanced transcytosis. In particular, the zombie mouse model bearing orthotopic ovarian cancer further validated DN@OEV presented high accumulation and penetration in tumor tissue by the transcytosis process. Our study indicated the strategy in enhancing transcytosis has significant implications for improving the therapeutic efficacy of the drug delivery system.

Janus particle-engineered structural lipiodol droplets for arterial embolization.

Embolization (utilizing embolic materials to block blood vessels) has been considered one of the most promising strategies for clinical disease treatments. However, the existing embolic materials have poor embolization effectiveness, posing a great challenge to highly efficient embolization. In this study, we construct Janus particle-engineered structural lipiodol droplets by programming the self-assembly of Janus particles at the lipiodol-water interface. As a result, we achieve highly efficient renal embolization in rabbits. The obtained structural lipiodol droplets exhibit excellent mechanical stability and viscoelasticity, enabling them to closely pack together to efficiently embolize the feeding artery. They also feature good viscoelastic deformation capacities and can travel distally to embolize finer vasculatures down to 40 µm. After 14 days post-embolization, the Janus particle-engineered structural lipiodol droplets achieve efficient embolization without evidence of recanalization or non-target embolization, exhibiting embolization effectiveness superior to the clinical lipiodol-based emulsion. Our strategy provides an alternative approach to large-scale fabricate embolic materials for highly efficient embolization and exhibits good potential for clinical applications.

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.

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 Cell Membrane-Targeting Self-Delivery Chimeric Peptide for Enhanced Photodynamic Therapy and In Situ Therapeutic Feedback.

Nowadays, cell membrane-targeted therapy, which owns high antitumor efficacy by avoiding cell barriers, has received great attention. Here, a cell membrane-targeted self-delivery theranostic chimeric peptide CMP-PpIX is designed for simultaneously targeted photodynamic therapy (PDT) of tumor and real-time therapeutic feedback. Self-assembled CMP-PpIX nanoparticles can effectively accumulate in tumor by enhanced permeability and retention effect without additional vector. And this chimeric peptide CMP-PpIX has low background fluorescence, which is due to its relatively high intramolecular Förster resonance energy transfer (FRET) quenching efficiency between 5(6)-carboxyfluorescein (FAM) and 4-(dimethylaminoazo)-benzene-4-carboxylic acid (Dabcyl). More importantly, CMP-PpIX can be anchored on the tumor cell membrane for more than 8 h. Under irradiation, reactive oxygen species produced by CMP-PpIX directly damage cell membrane and rapidly induce apoptosis, which significantly improve the efficacy of PDT in vitro and in vivo. Then, peptide sequence Asp-Glu-Val-Asp (DEVD) is subsequently cleaved by activated caspase-3 and activated caspase-7, which separates the FAM and Dabcyl and terminates the FRET process. Therefore, fluorescence of FAM is recovered to monitor the expression of activated caspase-3 in vitro and in vivo to feedback real-time PDT therapeutic efficacy. In general, a novel cell membrane-targeted self-delivery theranostic chimeric peptide offers new promise for effective imaging-guided PDT.

Evaluation of in vitro toxicity of silica nanoparticles (NPs) to lung cells: Influence of cell types and pulmonary surfactant component DPPC.

Cultured human lung epithelial cells, particularly A549 cells, are commonly used as the in vitro model to evaluate the inhalational toxicity of nanoparticles (NPs). However, A549 cells are cancer cells that might not reflect the response of normal tissues to NP exposure. In addition, the possible influence of pulmonary surfactant also should be considered. This study used silica NPs as model NPs, and evaluated the toxicity of silica NPs to both 16HBE human bronchial epithelial cells and A549 adenocarcinomic cells, with or without the presence of pulmonary surfactant component dipalmitoyl phosphatidylcholine (DPPC). We found that silica NPs induced cytotoxicity at the concentration of 128 µg/mL in 16HBE cells but not A5490 cells, and the cytotoxicity of silica NPs to 16HBE cells was inhibited by DPPC. Intracellular reactive oxygen species (ROS) was only induced in 16HBE cells, accompanying with decreased thiol levels. Moreover, 16HBE cells internalized more silica NPs compared with A549 cells, and the internalization was reduced with the presence of DPPC in both types of cells. The retention of ABC transporter substrate Calcein was only significantly induced by silica NPs at high concentrations in 16HBE cells, and was partially reduced due to the presence of DPPC. In addition, ABC transporter inhibitor MK571 increased the toxicity of silica NPs to both types of cells, with 16HBE cells being more sensitive. Our data revealed that the cell types and pulmonary surfactant components could influence the toxicological consequences of silica NPs to human lung cells. Therefore, it is recommended that in vitro studies should carefully select suitable models to evaluate the inhalational toxicity of NPs.