Engineering blood exosomes for tumor-targeting efficient gene/chemo combination therapy

Abstract

Rationale: Developing an effective nanoplatform to realize 'multi-in-one' is essential to broaden the therapeutic potential of combination therapy. Exosomes are ideal candidates since their intrinsic abilities of integrating multiple contents and functions. However, only limited efforts have been devoted to engineering exosomes to integrate the needed properties, also considering the safety and yield, for tumor-targeted and efficient gene/chemo combination therapy. Methods: Herein, by manipulating the exosome membrane, blood exosomes with high abundance and safety are engineered as a versatile combinatorial delivery system, where the doxorubicin (Dox) and cholesterol-modified miRNA21 inhibitor (miR-21i) are co-embedded into the lipid bilayer of exosomes, and the magnetic molecules and endosomolytic peptides L17E are bind to the exosome membrane through ligand-receptor coupling and electrostatic interactions, respectively. Results: It is proved that such engineering strategy not only preserves their intrinsic features, but also readily integrates multiple properties of tumor targeting, efficient transfection and gene/chemo combination therapy into blood exosomes. The lipid bilayer structure of exosomes allows them to co-load Dox and miR-21i with high-payloads. Moreover, profiting from the integration of magnetic molecules and L17E peptides, the engineered exosomes exhibit an enhanced tumor accumulation and an improved endosome escape ability, thereby specifically and efficiently delivering encapsulated cargos to tumor cells. As a result, a remarkable inhibition of tumor growth is observed in the tumor-bearing mice, and without noticeable side effects. Conclusions: This study demonstrates the potential of engineered blood exosomes as feasible co-delivery nanosystem for tumor-targeted and efficient combination therapy. Further development by replacing the drugs combined regimens can potentially make this engineered exosome become a general platform for the design of safe and effective combination therapy modality.

Extracellular Vesicles: “Stealth Transport Aircrafts” for Drugs

“…Significant tumor growth inhibitory effects were observed in tumor-bearing mice. There were no obvious side effects [30].…”

“…In addition, researchers are also committed to modifying the surfaces of EVs to improve their targeting. Many results show that this strategy can indeed improve the therapeutic effect of engineered EVs [30][31][32][33].…”

“…The researchers combined ligand-coupled superparamagnetic nanoparticles with specific membrane proteins of blood exosomes to achieve the separation, purification and tumor targeting of exosomes [30]. The chemotherapy drug doxorubicin (Dox) and the cholesterol-modified single-stranded miRNA-21 inhibitor (chol-miR21i) were co-loaded onto the exosomes.…”

“…Then the cationic endolysin peptide was absorbed on the negatively charged membrane surface of exosomes to promote the cytoplasmic release of the packaged cargo (Figure 1). The research results showed that these effectively released drugs and RNA simultaneously interfered with nuclear DNA activity and down-regulated the expression of oncogenes, thereby significantly inhibiting tumor growth and reducing side effects [30].…”

“…Blood EVs mainly secreted by reticulocytes (RTC) are a potential source of safe and sufficient EVs. Because they integrate various membrane proteins including Transferrin (Tf) receptors, but they do not have any immune and cancer stimulating activity [30]. Red blood cell EVs (RBCEV) also have the following advantages: large load; low self-nucleic acid content (red blood cells without nucleus and mitochondria); they can be delivered to a variety of different organs and tissues; large quantities of raw materials and easily available (the raw materials for producing RBCEVs are mainly O-type Blood of blood donors).…”