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Gene-editing cancer drugs delivery through Lipid based Nanoparticles

Solid tumors enclose themselves with a strong, impenetrable wall of molecular defenses as they develop. That barricade is notoriously tough to get around with drugs. In order to target cancer cells, scientists at UT Southwestern have now created nanoparticles that can penetrate the physical barriers around tumours. When the nanoparticles get inside, they release their payload, a gene editing mechanism that modifies the tumor's DNA to stop its growth and stimulate the immune system.

The growth and spread of liver and ovarian cancers in mice were substantially halted by the novel nanoparticles, as published in Nature Nanotechnology. According to study leader Daniel Siegwart, Ph.D., Associate Professor of Biochemistry at UT Southwestern, the system offers a fresh direction for the application of the gene-editing tool CRISPR-Cas9 in the treatment of cancer.

The low effectiveness of delivering payloads into tumors has significantly hampered the technology, despite the fact that CRISPR offers a novel method for treating cancer, according to Dr. Siegwart, a staff member of the Harold C. Simmons Comprehensive Cancer Center.

Researchers now have a technique to selectively edit the DNA within living cells thanks to CRISPR-Cas9 technology. Despite the gene editing system's promise to change the genes responsible for cancer development, getting CRISPR-Cas9 to solid tumors has proven to be difficult.

Dr. Siegwart and his colleagues have been researching and developing lipid nanoparticles (LNPs), tiny spheres of fatty molecules that may transport molecular payload into the human body, including the most current mRNA COVID-19 vaccines. The field had been constrained by the difficulty of directing nanoparticles to particular tissues until Dr. Siegwart's team demonstrated it in 2020.

The researchers started with nanoparticles that they had already modified to travel to the liver in the new effort to target cancer. They included a tiny amount of RNA (short interfering RNA, or siRNA) that may turn off focal adhesion kinase (FAK), a gene that is essential for maintaining the structural integrity of several cancers' physical defenses.

Targeting FAK opens the door for immune cells to enter the tumor, according to Di Zhang, Ph.D., a postdoctoral research fellow at UTSW and the paper's first author. "Targeting FAK not only weakens the wall around tumours and makes it simpler for the nanoparticles themselves to enter the tumour, but also paves the way for immune cells to enter."

Researchers incorporated CRISPR-Cas9 technology that might modify the PD-L1 gene inside freshly created nanoparticles. High quantities of the PD-L1 protein, which inhibits the immune system's capacity to combat tumors, are produced by many malignancies using this gene. Scientists have previously demonstrated that, in some malignancies, altering the PD-L1 gene can remove the brakes and allow a person's immune system to eradicate cancer cells.

The novel nanoparticles were examined in four animal models of ovarian and liver cancer by Drs. Siegwart, Zhang, and his associates. First, they demonstrated that by including siRNA to turn off FAK, the matrix of molecules around the tumours became less rigid and more permeable than usual. The tumour cells were subsequently examined, and it was discovered that numerous other nanoparticles had successfully altered the PD-L1 gene.

The researchers discovered that tumors 
in mice treated with nanoparticles that targeted both FAK and PD-L1 decreased to around one-eighth their original size. Tumors treated just with empty nanoparticles did not experience this reduction. Additionally, more immune cells invaded the tumors, and treated mice lived roughly twice as long on average.

To demonstrate the safety and effectiveness of the nanoparticles in various tumor types, more research is required. The therapy, according to the researchers, might be helpful in addition to current cancer immunotherapies that try to employ the immune system to fight tumors.

"We're all curious about what more LNPs can do after the COVID-19 LNP vaccinations were a global success. In order to improve cancer treatment outcomes, we created novel LNPs that can transport various genetic medicines at once. There is undoubtedly a tremendous deal of potential for LNP medications to treat many disorders, "Dr. Siegwart added.

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