Intranasal Delivery and Transfection of mRNA Therapeutics in the Brain Using Cationic Liposomes

Abstract

Nucleic acid-based therapeutics, including the use of messenger RNA (mRNA) as a drug molecule, has tremendous potential in the treatment of chronic diseases, such as age-related neurodegenerative diseases. In this study, we have developed a cationic liposomal formulation of mRNA and evaluated the potential of intranasal delivery to the brain in murine model. Preliminary in vitro studies in J774A.1 murine macrophages showed GFP expression up to 24 h and stably expressed GFP protein in the cytosol. Upon intranasal administration of GFP-mRNA/cationic liposomes (3 mg/kg dose) in mice, there was significantly higher GFP-mRNA expression in the brain post 24 h as compared to either naked mRNA or the vehicle-treated group. Luciferase mRNA encapsulated in cationic liposomes was used for quantification of mRNA expression distribution in the brain. The results showed increased luciferase activity in the whole brain in a dose-dependent manner. Specifically, the luciferase-mRNA/ cationic liposome group (3 mg/kg dose) showed significantly higher luciferase activity in the cortex, striatum, and midbrain regions as compared with the control groups, with minimal systemic exposure. Overall, the results of this study demonstrate the feasibility of brain-specific, nonviral mRNA delivery for the treatment of various neurological disorders.

From COVID-19 to Cancer mRNA Vaccines: Moving From Bench to Clinic in the Vaccine Landscape

“…Liposomes are membrane-bound structures that can be produced through the self-assembly process (78). Dhaliwal et al used liposomes for mRNA delivery, and cationic liposomes are the preferred system (79). Due to rapid elimination, cationic lipid delivery systems are very challenging (80).…”

“…Dhaliwal et al. used liposomes for mRNA delivery, and cationic liposomes are the preferred system ( 79 ). Due to rapid elimination, cationic lipid delivery systems are very challenging ( 80 ).…”

Multicompartment Polymeric Nanocarriers for Biomedical Applications

“…[6,57] These multicompartment systems are of interest as they combine physicochemical properties of both liposomes and polymer capsules while minimizing some limitations associated with each system. Liposomes are natural lipid carriers which have potential to encapsulate a variety of small therapeutic cargoes including enzymes, [58] nucleic acids, [59,60] anticancer drugs, [61][62][63] proteins, [64,65] and imaging agents. [66,67] However, they can be prone to leakage.…”

The New Frontiers in Neurodegenerative Diseases Treatment: Liposomal-Based Strategies

“…Recently, another work (Dhaliwal et al, 2020) reported how it is possible to take advantage of cationic LPs to improve the mRNA delivery. After optimization of the liposomal formulation, mRNA was administered by intranasal route to CD-1 mice.…”