meChemotherapy has at least two shortcomings: It can harm healthy cells as well as cancerous ones, and it can have difficulty reaching therapeutic targets that hide within cancer cells. To get around these shortcomings, biomedical engineers at Binghampton University collaborated with colleagues in China to develop nanovesicles that can target cancer cells and deliver treatments directly.

These biomedical engineers are among those researching the use of cell-derived nanovesicles to deliver therapeutic agents to the interior of cancer cells with better accuracy and efficiency. The small sacks of proteins, lipids, and RNA that cells secrete as a method of intercellular communication could be modified to carry medications.

“These nanocarriers have some excellent properties,” said Yuan Wan, an assistant professor at Binghampton. “For example, they can be harvested from human cell strains, so the immune response is very low. That allows for optimal biocompatibility, so they evade immune clearance and have an extended blood half-life. The time for circulation around the body is maybe 45 seconds, so the drug-loaded nanovesicles can safely travel to the tumors many times and the drugs have more chances to be taken up by cancer cells compared to drugs freely introduced into the body.

“Large amounts of encapsulated drugs can be well protected and retained by the nanovesicles’ lipid membranes. Once cancer cells uptake these nanovesicles, high drug concentrations in the tumor microenvironment effectively kill cancer cells. In comparison, free drugs can diffuse quickly and then are cleaned from the body. Only a very tiny amount of drugs reaches the tumors, making treatment efficacy very low. You can increase the dose, but a higher dose also results in high systematic toxicity.”

Wan is a corresponding author of a study that recently appeared in Nature Communications. The study reports “a bioinspired material, engineered fusogen and targeting moiety co-functionalized cell-derived nanovesicle (CNV) called eFT-CNV, as a drug vehicle.” To unpack this dense cluster of words, keep in mind that a fusogen is a protein that facilitates cancer targeting and the fusion of cell membranes, and be informed that the targeting moiety is anti-GPC3 scFv, which is a construct that incorporates an antibody that binds to GPC3, a protein expressed by cancer cells. Basically, the eFT-CNV is engineered to be studded with fusogens and anti-GPC3 scFv molecules.

“We show that universal eFT-CNVs can be produced by extrusion of genetically modified donor cells with high yield and consistency,” the article’s authors wrote. “We demonstrate that bioinspired eFT-CNVs can efficiently and selectively bind to targets and trigger membrane fusion, fulfilling endo-lysosomal escape and cytosolic drug delivery. We find that, compared to counterparts, eFT-CNVs significantly improve the treatment efficacy of drugs acting on cytosolic targets.”

Schematic of anti-GPC3 scFv and engineered fusogen co-expressing eFT-CNVs for cytosolic delivery of therapeutics. [Nature Communications]
Overexpressed or cancer-specific antigens that occur in malignant cells are recognized and bound by eFT-CNVs that encapsulate anticancer drugs. Then the eFT-CNVs inject the drugs into the cancer cells. The eFT-CNVs, it should be emphasized, are designed to leave healthy cells alone.

“People widely use nanocarriers known as polymer-decorated liposomes, and they are already approved by the FDA,” Wan said. “But they are not perfect, because they do not have any cancer-targeting effect and may have very severe immunogenicity issues [triggering a response by the immune system].”

In 2021, Wan received a $2.4 million grant from the National Institutes of Health to test plasma-derived extracellular vesicles to diagnose whether solitary pulmonary nodules found in human lungs are benign or malignant. By leveraging that grant, this current but separate research harnesses nanovesicles engineers them so that they are specific in what they affect. Ideally, doctors could prepare these targeting moieties and fusogen co-equipped nanovesicles for use in safer vaccine delivery and genetic engineering.

As for what’s next, Wan said: “We need to show treatment efficacy in large animal models and demonstrate that we don’t need a large amount of vesicles because we’ll have the membrane fusion function. If you lower the number of vesicles and drugs you need, you lower the cost of the treatment and the side effects.”

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