Systemic Brain Delivery of Oligonucleotide Therapeutics Enhanced by Protein Corona‐Assisted DNA Cubes

Abstract

The systemic delivery of oligonucleotide therapeutics to the brain is challenging but highly desirable for the treatment of brain diseases undruggable with traditional small‐molecule drugs. In this study, a set of DNA nanostructures is prepared and screened them to develop a protein corona‐assisted platform for the brain delivery of oligonucleotide therapeutics. The biodistribution analysis of intravenously injected DNA nanostructures reveals that a cube‐shaped DNA nanostructure (D‐Cb) can penetrate the brain‐blood barrier (BBB) and reach the brain tissue. The brain distribution level of D‐Cb is comparable to that of other previous nanoparticles conjugated with brain‐targeting ligands. Proteomic analysis of the protein corona formed on D‐Cb suggests that its brain distribution is driven by endothelial receptor‐targeting ligands in the protein corona, which mediate transcytosis for crossing the BBB. D‐Cb is subsequently used to deliver an antisense oligonucleotide (ASO) to treat glioblastoma multiforme (GBM) in mice. While free ASO is unable to reach the brain, ASO loaded onto D‐Cb is delivered efficiently to the brain tumor region, where it downregulates the target gene and exerts an anti‐tumor effect on GBM. D‐Cb is expected to serve as a viable platform based on protein corona formation for systemic brain delivery of oligonucleotide therapeutics.