Systemically Injected Exosomes Targeted to EGFR Deliver Antitumor MicroRNA to Breast Cancer Cells

Abstract

Despite the therapeutic potential of nucleic acid drugs, their clinical application has been limited in part by a lack of appropriate delivery systems. Exosomes or microvesicles are small endosomally derived vesicles that are secreted by a variety of cell types and tissues. Here, we show that exosomes can efficiently deliver microRNA (miRNA) to epidermal growth factor receptor (EGFR)-expressing breast cancer cells. Targeting was achieved by engineering the donor cells to express the transmembrane domain of platelet-derived growth factor receptor fused to the GE11 peptide. Intravenously injected exosomes delivered let-7a miRNA to EGFR-expressing xenograft breast cancer tissue in RAG2(-/-) mice. Our results suggest that exosomes can be used therapeutically to target EGFR-expressing cancerous tissues with nucleic acid drugs.

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

“…One method commonly used to modify the surface proteins of EVs is called the “binding method,” which involves combining the “cargo” protein with a protein localized on the surface of the EVs by gene modification 20, 105, 106, 107. Already used binding segments include the C1C2 domain of milk fat globule‐EGF factor 8 protein,105, 106 the transmembrane domain of platelet‐derived growth factor receptor,107 and the extraexosomal N‐terminal of Lamp2b 20.…”

“…Already used binding segments include the C1C2 domain of milk fat globule‐EGF factor 8 protein,105, 106 the transmembrane domain of platelet‐derived growth factor receptor,107 and the extraexosomal N‐terminal of Lamp2b 20. Another method is called the “membrane‐anchored method” and involves anchoring the “cargo” protein to the membrane by fusing it to oligomeric membrane‐anchored proteins instead of certain EV‐related proteins 108.…”

“…Research has shown that most nanosized particles are eliminated by the liver and kidneys, or phagocytosed by macrophages 107. The purpose of surface protein modification is to specifically change the in vivo distribution by regulating the targeting ability of EVs to not only enhance the specific effects on target cells but also to reduce off‐target effects.…”

Biocompatibility of highly purified bovine milk‐derived extracellular vesicles

“…For example, exosomes derived from dendritic cells were modified by targeting peptide and used for the delivery of short interfering RNA (siRNA) into mouse brain [7]. Ohno et al achieved the delivery of anti-tumour microRNA (miRNA) to cancer cells in vitro and in vivo using exosomes from the HEK293 cells [8]. However, the yield of EVs from the conditioned medium is insufficient for clinical use.…”

Microfluidics‐based on‐a‐chip systems for isolating and analysing extracellular vesicles

“…However, there are several disadvantages to the use of synthetic nanoparticles, such as low biocompatibility, immunoreaction and safety problems [50]. In comparison, EV-based DDSs have several advantages, for example, (1) low toxicity[51,52], (2) good stability in the circulation [52,53], (3) specific targeting ability [51,52], (4) customisation of targeting ability by modifying surface proteins, for example, based on the C1C2 domain from the EV-surface-specific protein MFG-E8 (milk fat globule-epidermal growth factor 8 protein), or the N-terminus of lysosomal-associated membrane protein 2b (Lamp2b) [52,54] (Figure 1(e)) and (5) straightforward cargo loading, especially for biomacromolecules, based on cell engineering, which is particularly suitable for delivering nucleic acids, as well as providing specific delivery technology for proteins – for example, intracellular proteins labelled by a WW tag for the recognition by late-domain (L-domain) proteins and specifically loaded into EVs during their biogenesis [9,52] (Figure 1(f)). As a result, we believe that EVs will open up a new frontier in the field of regenerative medicine.…”