Advances in engineered exosomes towards cancer diagnosis and therapeutics

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Abstract

Exosomes have emerged as natural nanocarriers and are advantageous in the field of nanomedicine due to their lipid bilayer membrane comprising many proteins, nucleic acids and cell debris. Exosomes are secreted from all types of living cells and play a role in cancer diagnosis and therapy because of their biological properties, such as intercellular communication, modulation of immune responses, biocompatibility and target specificity. Many studies have shown that exosomes can be engineered or modified with different therapeutic substances, including nucleic acids, proteins, drugs and other nanomaterials, to improve their specificity, efficiency and safety in nanomedicine. In this review, we summarize the methodologies of exosome biogenesis, purification, the possible mechanisms of cellular uptake and the important role of exosomes in cancer diagnosis, followed by the role of engineered exosomes in cancer therapy. Also, future trends and challenges are discussed. We strongly suggest that a clear articulation of the fundamental principles for the creation of exosome-based theranostic platforms will help reveal the unique powers of exosomes in early cancer diagnosis and therapeutics, including chemotherapy, gene therapy, immunotherapy and phototherapy.

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Ror2 signaling regulates Golgi structure and transport through IFT20 for tumor invasiveness

Michiru Nishita, Seung-Yeol Park, Tadashi Nishio … (2017)

Signaling through the Ror2 receptor tyrosine kinase promotes invadopodia formation for tumor invasion. Here, we identify intraflagellar transport 20 (IFT20) as a new target of this signaling in tumors that lack primary cilia, and find that IFT20 mediates the ability of Ror2 signaling to induce the invasiveness of these tumors. We also find that IFT20 regulates the nucleation of Golgi-derived microtubules by affecting the GM130-AKAP450 complex, which promotes Golgi ribbon formation in achieving polarized secretion for cell migration and invasion. Furthermore, IFT20 promotes the efficiency of transport through the Golgi complex. These findings shed new insights into how Ror2 signaling promotes tumor invasiveness, and also advance the understanding of how Golgi structure and transport can be regulated.

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The biology, function, and biomedical applications of exosomes

Raghu Kalluri, Valerie LeBleu (2020)

The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.

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Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.

Hadi Valadi, Karin Ekström, Apostolos Bossios … (2007)

Exosomes are vesicles of endocytic origin released by many cells. These vesicles can mediate communication between cells, facilitating processes such as antigen presentation. Here, we show that exosomes from a mouse and a human mast cell line (MC/9 and HMC-1, respectively), as well as primary bone marrow-derived mouse mast cells, contain RNA. Microarray assessments revealed the presence of mRNA from approximately 1300 genes, many of which are not present in the cytoplasm of the donor cell. In vitro translation proved that the exosome mRNAs were functional. Quality control RNA analysis of total RNA derived from exosomes also revealed presence of small RNAs, including microRNAs. The RNA from mast cell exosomes is transferable to other mouse and human mast cells. After transfer of mouse exosomal RNA to human mast cells, new mouse proteins were found in the recipient cells, indicating that transferred exosomal mRNA can be translated after entering another cell. In summary, we show that exosomes contain both mRNA and microRNA, which can be delivered to another cell, and can be functional in this new location. We propose that this RNA is called "exosomal shuttle RNA" (esRNA).