Fig. 3. Overcoming challenges in the development of RNA therapeutics.

A Common chemical modifications. RNA-based drugs often have various chemical modifications, including 5′-and 3′-end conjugates, 2′-sugar substitution and internucleoside linkage modifications. B Nanocarriers delivery strategies. Five representative nanocarriers are shown: (①) Lipid nanoparticles encapsulating nucleic acids. (②) Cationic polymers electrostatically bind to negatively-charged nucleic acids to form polyplexes. (③) Engineered exosomes with aptamers or therapeutic RNAs on the outer surface. (④) Spherical nucleic acid nanoparticle consisting of an inorganic core coated in densely packed oligonucleotides attached by chemical linkages. (⑤) Self-assembled DNA cage tetrahedron nanostructure. Oligonucleotide drugs can be incorporated into the design of the DNA cage itself. Additional targeting ligands and polyethylene glycol (PEG) can be further conjugated to the nanostructure. These nanocarriers can deliver RNA molecules through binding to the cell membrane, endocytosis, endosome escape and RNAs are released in the cytoplasm and translation to proteins or incorporated into corresponding ribonucleoprotein complexes to silence target transcripts.