Researchers at the Massachusetts Institute of Technology (MIT) have developed lipid nanoparticles that deliver messenger RNA (mRNA) directly to natural killer (NK) cells, generating functional chimeric antigen receptor (CAR) NK cells inside the body. The approach eliminated tumors in mouse models of cancer and reduced liver damage in a model of autoimmune hepatitis.
The study describes a targeted delivery system that could expand the applications of CAR-based immunotherapy while avoiding the need to extract and genetically modify immune cells in a laboratory.
Unlike approaches that permanently modify immune-cell DNA, the platform uses mRNA to produce temporary CAR expression. The researchers developed lipid nanoparticles (LNPs) coated with engineered antibody fragments that recognize receptors on NK cells, achieving delivery efficiencies of up to approximately 80 percent in mice.
CAR expression peaked approximately 24 hours after administration and became nearly undetectable by 72 hours, suggesting that repeated dosing may be needed to sustain therapeutic activity.
“The idea here is you can deliver a nanoparticle that will modify your own NK cells with a CAR construct and teach them to attack tumor cells,” said senior author Daniel Anderson in a press release.
In a humanized mouse model of B-cell lymphoma, five doses of nanoparticles carrying mRNA for a CD19-directed CAR produced complete tumor remission in all five treated animals, with efficacy comparable to CAR NK cells manufactured outside the body.
The platform also demonstrated activity against T-cell leukemia and melanoma. In a mouse model of autoimmune hepatitis, nanoparticles delivering a CD3-directed CAR alongside interleukin-15 reduced autoreactive T-cell populations, improved liver enzyme levels, and limited liver damage.
NK cells may offer particular advantages for treating T-cell malignancies and autoimmune disorders. CAR T cells engineered to recognize antigens shared by healthy T cells can attack one another, a phenomenon known as fratricide. CAR NK cells could provide an alternative for targeting these cell populations.
Generating CAR NK cells directly inside the body could also reduce the manufacturing complexity associated with conventional cell therapies, which require immune cells to be collected, modified, expanded, and reinfused into patients.
Although repeated nanoparticle administration was generally well tolerated in mice, the researchers detected antibodies against the targeting fragments.
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