Hybrid exosomes, exosome-like nanovesicles and engineered exosomes for therapeutic applications.

Extracellular vesicles (EVs) are excellent potential vectors for the delivery of therapeutic drugs. However, issues with biological safety and disease targeting substantially limit their clinical application. EVs from red blood cells (RBC-EVs) are potential drug delivery vehicles because of their unique biological safety. Here, we demonstrated that EVs, including RBC-EVs, show natural liver accumulation. Mechanistically, the liver environment induces macrophages to phagocytize RBC-EVs in a C1q-dependent manner. RBC-EVs loaded with antisense oligonucleotides of microRNA-155 showed macrophage-dependent protective effects against acute liver failure (ALF) in a mouse model. These RBC-EVs were also effective in treatment of ALF. Furthermore, compared to routine doses of doxorubicin and sorafenib (SRF), RBC-EVs loaded with doxorubicin or SRF showed enhanced therapeutic effects on a murine model of orthotopic liver cancer through a mechanism dependent on macrophages. Importantly, drug-loaded RBC-EVs showed no systemic toxicity at therapeutically effective doses, whereas routine doses of doxorubicin and SRF showed obvious toxicity. Thus, drug-loaded RBC-EVs hold high potential for clinical applications in the treatment of liver disease therapy.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jev2.12030

Extracellular vesicles: Natural liver-accumulating drug delivery vehicles for the treatment of liver diseases.

Background Hepatocellular carcinoma (HCC) is one of the most common malignancies globally. Despite aggressive and multimodal treatment regimens, the overall survival of HCC patients remains poor. MAIN: Circular RNAs (circRNAs) are noncoding RNAs (ncRNAs) with covalently closed structures and tissue- or organ-specific expression patterns in eukaryotes. They are highly stable and have important biological functions, including acting as microRNA sponges, protein scaffolds, transcription regulators, translation templates and interacting with RNA-binding protein. Recent advances have indicated that circRNAs present abnormal expression in HCC tissues and that their dysregulation contributes to HCC initiation and progression. Furthermore, researchers have revealed that some circRNAs might serve as diagnostic biomarkers or drug targets in clinical settings. In this review, we systematically evaluate the characteristics, biogenesis, mechanisms and functions of circRNAs in HCC and further discuss the current shortcomings and potential directions of prospective studies on liver cancer-related circRNAs. Conclusion CircRNAs are a novel class of ncRNAs that play a significant role in HCC initiation and progression, but their internal mechanisms and clinical applications need further investigation.

/pdf/circular-rnas-characteristics-biogenesis-mechanisms-and-1qi5xoyvp3.pdf

Circular RNAs: characteristics, biogenesis, mechanisms and functions in liver cancer.

Extracellular vesicles (EVs) such as ectosomes and exosomes have gained attention as promising natural carriers for drug delivery. Exosomes, which range from 30 to 100 nm in diameter, possess a lipid bilayer and are secreted by various cells. Due to their high biocompatibility, stability, and low immunogenicity, exosomes are favored as cargo carriers. The lipid bilayer membrane of exosomes also offers protection against cargo degradation, making them a desirable candidate for drug delivery. However, loading cargo into exosomes remains to be a challenge. Despite various strategies such as incubation, electroporation, sonication, extrusion, freeze–thaw cycling, and transfection that have been developed to facilitate cargo loading, inadequate efficiency still persists. This review offers an overview of current cargo delivery strategies using exosomes and summarizes recent approaches for loading small-molecule, nucleic acid, and protein drugs into exosomes. With insights from these studies, we provide ideas for more efficient and effective delivery of drug molecules by using exosomes.

/pdf/current-strategies-for-exosome-cargo-loading-and-targeting-11ciqmtj.pdf

Current Strategies for Exosome Cargo Loading and Targeting Delivery

Exploring interactions between extracellular vesicles and cells for innovative drug delivery system design.

UBE2M-mediated neddylation of TRIM21 regulates obesity-induced inflammation and metabolic disorders.

Abstract PD-L1 + tumor-derived extracellular vesicles (TEVs) cause systemic immunosuppression and possibly resistance to anti-PD-L1 antibody (αPD-L1) blockade. However, whether and how PD-L1 + TEVs mediate αPD-L1 therapy resistance is unknown. Here, we show that PD-L1 + TEVs substantially decoy αPD-L1 and that TEV-bound αPD-L1 is more rapidly cleared by macrophages, causing insufficient blockade of tumor PD-L1 and subsequent αPD-L1 therapy resistance. Inhibition of endogenous production of TEVs by Rab27a or Coro1a knockout reverses αPD-L1 therapy resistance. Either an increased αPD-L1 dose or macrophage depletion mediated by the clinical drug pexidartinib abolishes αPD-L1 therapy resistance. Moreover, in the treatment cycle with the same total treatment dose of αPD-L1, high-dose and low-frequency treatment had better antitumor effects than low-dose and high-frequency treatment, induced stronger antitumor immune memory, and eliminated αPD-L1 therapy resistance. Notably, in humanized immune system mice with human xenograft tumors, both increased αPD-L1 dose and high-dose and low-frequency treatment enhanced the antitumor effects of αPD-L1. Furthermore, increased doses of αPD-L1 and αPD-1 had comparable antitumor effects, but αPD-L1 amplified fewer PD-1 + Treg cells, which are responsible for tumor hyperprogression. Altogether, our results reveal a TEV-mediated mechanism of αPD-L1-specific therapy resistance, thus providing promising strategies to improve αPD-L1 efficacy. 

/pdf/tumor-extracellular-vesicles-mediate-anti-pd-l1-therapy-8k3gyjqt.pdf

Tumor extracellular vesicles mediate anti-PD-L1 therapy resistance by decoying anti-PD-L1

Tumor-derived extracellular vesicles: Regulators of tumor microenvironment and the enlightenment in tumor therapy.

The invention discloses a medicine carrying red blood cell exosome, an application thereof and liver disease medicines. The medicine carrying red blood cell exosome is obtained by importing medicinesfor treating liver diseases into a red blood cell exosome. Through research, the inventor finds that the red blood cell exosome has liver chemotaxy without any modification, the exosome of red blood cell sources solves the problem of yield of the exosome, the red blood cells do not contain DNA and RNA, and the exosome is used for decades for clinical blood transfusion. Compared with the exosome ofother cell sources, the medicine carrying red blood cell exosome has good application prospects, target medication can be realized, the treatment effect on liver relevant diseases can be increased, and the toxic and side effect of the medicines can be reduced.

Medicine carrying exosome, application thereof and liver disease medicines

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