Exosome Nanocarriers for Tumor Treatment

Cancer is an important cause of death in humans. Current treatments such as radiotherapy and chemotherapy are often accompanied by significant side effects and drug resistance. Nanomedicine has become the preferred solution for improving biocompatibility and biodegradable systems. Nowadays, nanoparticles are not only widely used in treatment, but also show great potential in the field of diagnosis. Exosomes as nanocarriers have the characteristics of high biocompatibility, low immunogenicity and excellent penetration ability, and have broad development prospects in tumor diagnosis and treatment.

Exosomes were first discovered in 1986. They are nanoscale (40-150 nm) small extracellular vesicles secreted by various cells. Cell membrane proteins and extracellular components fuse with each other to form endosomes. The further formed multivesicular bodies (MVBs) fuse with the cell membrane and are released to become exosomes. Several specific surface molecular markers such as CD9, CD63, CD81, and CD82 can all show the existence of exosomes. Exosomes can deliver proteins, lipids, and nucleic acids (DNA, mRNA, miRNA, cRNA, and lncRNAs) as carriers. Cell exosomes are responsible for cell-to-cell communication and horizontal transfer of genetic information between cells. Initially, exosomes were only regarded as cellular metabolic products. It was not until 1996 that G. Raposo discovered that a B-cell-derived exosome could stimulate effector CD4 cells to produce anti-tumor responses, and the role of exosomes in tumor treatment was discovered. Nearly 20 years later, American scientist James E. Rothman, Randy W. Schekmán and German scientist Thomas C. Südho jointly won the 2013 Nobel Prize in Physiology or Medicine for discovering the regulatory mechanism of vesicle transport in cells. As a type of vesicle, exosomes have become a rising star in immunotherapy. Since Nature’s report on exosome GPC1 as a marker for pancreatic cancer, scholars’ interest in exosome research has increased rapidly. At first, the function and marker research of exosomes dominated the mainstream, and tumor-derived exosome nucleic acids and proteins became reliable tumor diagnostic markers. As the inherent ability of exosomes to “communicate and shuttle” between cells and signal transduction and their stable physiological characteristics are known to researchers, they have gradually become excellent drug delivery carriers.

Exosomes as a Tumor Drug Delivery System

Exosomes are a natural nano-drug delivery system derived from body fluids. They have excellent drug targeting, low toxicity and stability, and their potential in drug delivery and tumor treatment has attracted much attention. Various adhesion proteins are expressed on the surface of exosomes, which can promote protein-membrane fusion and bind to specific receptors in receptor cells. The drugs to be delivered are encapsulated into purified exosomes by incubation, ultrasonic treatment and electroporation. Exosomes deliver loaded drugs to specific receptor cells and have been developed as drug delivery carriers for nucleic acids and small molecule drugs.

Exosomes Deliver Small Molecule Drugs

Exosomes have high biocompatibility and can be used as nanocarriers for tissue-specific targeted delivery. Drugs can be encapsulated in exosomes, thereby extending the half-life of drugs and improving the stability of drug release. Exosomes can be loaded with small molecule chemotherapeutic drugs, such as paclitaxel (PTX), doxorubicin (DOX), curcumin, etc. Curcumin is a good drug for cancer treatment, but due to its low water solubility, it has a low utilization rate. Researchers have developed a method to extract exosomes from milk to encapsulate curcumin, which significantly enhances its stability, solubility and bioavailability, and exerts the potential of exosomes encapsulating chemotherapy drugs in cancer treatment. Macrophage-derived exosomes show the property of preferential aggregation in tumor cells. Exosomes (231-Exo) are specifically internalized by non-small cell lung cancer through the interaction between the expression of integrin β4 and tumor cell surface protein C (SPC). miRNA-126 is loaded in the exosome carrier (miR-126: 231-Exo) and blocks the PTEN/PI3K/AKT signaling pathway to inhibit cell proliferation and migration. In addition, some researchers have used a biocompatible tumor cell exosome biomimetic porous silicon nanoparticle (PSiNPs) as a drug carrier for targeted cancer chemotherapy. Exosomes coated with doxorubicin loaded PSiNPs showed vascular extravasation and penetration into the deep parenchyma of the tumor after intravenous administration to produce a strong anti-cancer effect. In summary, the natural biocompatibility of exosomes makes it an effective drug delivery tool. From this, we can conclude that exosomes can not only transport drugs, but also increase drug half-life, reduce toxicity, and even overcome various barriers.

Exosome Delivery of Nucleic Acid Molecules

Studies have shown that exosomes can carry nucleic acid macromolecules and small molecules. Traditional bacterial plasmids, phage plasmids, and lentiviral vectors have limitations due to factors such as biological toxicity and immunogenicity. Exosomes have become promising nanomaterials in nucleic acid-based tumor therapeutics. In order to increase the nucleic acid loading capacity and targeted modification, researchers have invented cell nano-biochips to promote the release of exosomes containing therapeutic mRNA and targeting peptides. The number of exosomes produced is 50 times more than that of overall electroporation and other exosome production strategies, which has opened up a new way to mass produce therapeutic mRNA exosomes. In combined siRNA therapy, researchers designed a biomimetic nanoparticle coated with cationic bovine serum albumin and S100A4 siRNA exosome membrane, which has higher targeting for triple-negative breast cancer and can protect siRNA from degradation. Exosomes can also be used as carriers of CRISPR/Cas9 plasmids. Tumor-derived exosomes are used to load the CRISPR/Cas9 system, which selectively accumulates in ovarian cancer tumors of SKOV3 xenograft mice, inhibiting polymerase-1 (PARP-1) expression and promoting apoptosis of ovarian cancer cells. At the same time, using exosomes to load Cas9 protein can effectively target the blood-brain barrier and improve gene editing efficiency. The above studies show that exosomes are excellent carriers for the effective transportation of nucleic acid molecules. Exosomes can be engineered to increase their load and delivery efficiency. The advantages of exosomes as nucleic acid delivery carriers will continue to be brought into play.