Abstract
We previously reported that macropinocytosis (accompanied by actin reorganization, ruffling of the plasma membrane, and engulfment of large volumes of extracellular fluid) is an important process for the cellular uptake of extracellular vesicles, exosomes. Accordingly, we developed techniques to induce macropinocytosis by the modification of biofunctional peptides on exosomal membranes, thereby enhancing their cellular uptake. Arginine-rich cell-penetrating peptides have been shown to induce macropinocytosis via proteoglycans; accordingly, we developed peptide-modified exosomes that could actively induce macropinocytotic uptake by cells. In addition, the activation of EGFR induces macropinocytosis; based on this knowledge, we developed artificial leucine-zipper peptide (K4)-modified exosomes. These exosomes can recognize E3 sequence-fused EGFR (E3-EGFR), leading to the clustering and activation of E3-EGFR by coiled-coil formation (E3/K4), which induces cellular exosome uptake by macropinocytosis. In addition, modification of pH-sensitive fusogenic peptides (e.g., GALA) also enhances the cytosolic release of exosomal contents. These experimental techniques and findings using biofunctional peptides have contributed to the development of exosome-based intracellular delivery systems.
Highlights
Kin-ya TomizakiExtracellular vesicles (EVs), including exosomes and microvesicles, are secreted from most cells in the human body
We have previously developed and successfully demonstrated a novel drug delivery system based on biofunctional peptide-modified exosomes (Figure 1); this includes argininerich cell-penetrating peptide-modified exosomes for the active induction of macropinocytosis and effective intracellular delivery of therapeutic molecules, a pH-sensitive fusogenic peptide for enhanced cytosolic release of exosomal contents, and a receptor target system using artificial coiled-coil peptide-modified on exosomal membranes
The importance of macropinocytosis in the cellular uptake of exosomes and the methods for modification of biofunctional peptides on exosomes to induce macropinocytosis in targeted recipient cells have been discussed. Another active target system based on exosomes recently developed was summarized and discussed, and macropinocytosis induction might possibly contribute to improvement for the cellular uptake efficacy and biological efficiency in the system
Summary
Extracellular vesicles (EVs), including exosomes and microvesicles, are secreted from most cells in the human body. Exosomemediated delivery of miR-181c triggers the breakdown of the blood-brain barrier (BBB), leading to brain metastasis [4], and EVs encapsulating matrix metalloproteinase 1 mRNA have been observed in ovarian cancer metastasis [5]. Experimental techniques, such as molecular weight measurement, antibody-based detection, real-time polymerase chain reaction, and polymer-based reverse-phase glycoprotein array, have been used to detect EV-encapsulated miRNA and protein in cancer diagnosis [3]. Further interdisciplinary research in medical, pharmaceutical, engineering, and physicochemical fields to develop EV-delivery techniques will enable the intravital detection of disease progression and the manipulation of cellular functions
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