Researchers from the Massachusetts Institutes of Technology (MIT) have discovered that lipid nanoparticle-RNA can reduce inflammation in the brain, a hallmark symptom of Alzheimer’s disease (AD).
The study, published in the journal Advanced Materials, showed that different nanoparticles could be used to develop a potential therapy for AD as well as other neuroinflammatory diseases.
Researchers delivered small interfering RNA (siRNA) via a tailored lipid nanoparticle (LNP) formulation to reduce the expression of PU.1, a gene product associated with excessive inflammation in neurological conditions, in multiple mouse models using cultured human cells.
Previous studies have already demonstrated how blocking the consequences of PU.1 protein activity can help reduce AD-related neuroinflammation and pathology.
The team changed the structures of two of the four main components of LNPs and varied the ratio of lipids to RNA, producing seven formulations to test. After testing in a lab, they found that one of the seven formulations, MG-LNP, stood out for its high delivery efficiency and safety of a test RNA cargo.
The team then tested the formulations’ effectiveness and safety in mice via two methods of injection: into the body or into the cerebrospinal fluid (CSF).
Researchers found that injecting the MG-LNP formulation was most effective when injected into the CSF, which produced a greater efficacy in targeting the microglia, the brain’s immune cells, without affecting cells in other organs, compared to the body.
Researchers tested MG-LNP in two mouse models: one that exposed mice to the LPS molecule, which stimulates infection and systemic inflammation responses and the second in mice with a hyperactive enzyme called CDKG5.
They observed that the MG-LNP injection carrying the anti-PU.1 siRNA reduced the expression of PU.1 and achieved a reduction in inflammation by directly suppressing the expression of the Spi1 gene, which encodes PU.1.
In addition to this, the study demonstrated a new way to deliver RNA to microglia, which has been challenging to target.
The researchers explained that the findings “support the use of MG-LNP-mediated anti-PU.1 siRNA delivery as a potential therapy for neuroinflammatory diseases,” calling the results a “proof-of-principle”.
Before testing on human patients with neuroinflammatory diseases, further testing will be required.