Synthesis of amino ester functionalized self-neutralizing curdlan nanoparticles for brain targeted mRNA delivery

Aminated curdlan derivatives are excellent carriers for delivery of short interfering RNA (siRNA), but their efficiency for mRNA delivery has not been explored. Degradable polymers like poly(β-amino ester) can deliver mRNA due to their biodegradability which is essential for timely release of mRNA cargo upon entering the cell. Herein, we report the synthesis of curdlan derivatives bearing α- or β-amino ester branches for brain targeted mRNA delivery. The β-amino ester functionalized curdlan (denoted by 6AC-MEP) efficiently encapsulated mRNA to form polymeric nanoparticles (PNPs), which readily entered neural cells and initiated the expression of cargo mRNA in vitro . In mouse traumatic brain injury (TBI) model, systemic administration of 6AC-MEP PNPs carrying luciferase mRNA resulted in the strong luminescent signal in the perilesional region of the brain. Two consecutive administrations of 6AC-MEP PNPs loaded with brain-derived neurotrophic factor (BDNF) mRNA resulted in strong expression of BDNF in the ipsilateral hemisphere of TBI mouse brain. The overexpression of BDNF in the brain reduced TBI-induced edema in the brain and improved cognitive function. Taken together, our data suggested 6AC-MEP PNP is a promising carrier for targeted delivery of therapeutic mRNAs.