Fig. 4. Oligonucleotide delivery strategies.

Schematics of various delivery strategies for small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs). a | Lipid–siRNA conjugate wherein cholesterol is conjugated to the 3ʹ terminus of the passenger strand. b | Triantennary N-acetylgalactosamine (GalNAc) moiety conjugated to an ASO. c | Antibody–siRNA conjugate. Oligonucleotides can be attached to the antibody or Fab fragment using click chemistry or thiol–maleimide linkages. d | Aptamer–siRNA conjugate. In vitro transcription can be used to generate a chimaeric aptamer–passenger strand as a single molecule. e | Peptide–ASO conjugate. The example is a PMO (phosphorodiamidate morpholino oligonucleotide) conjugated to a cell-penetrating peptide (Pip–9b2)²⁰⁹. f | Stable nucleic acid lipid particle encapsulating siRNAs. g | Engineered exosome with the brain-targeting rabies virus glycoprotein (RVG) peptide displayed on the outer surface²⁵⁵. The exosome consists of a membrane containing lipids and proteins derived from the donor cell. The exosome also contains therapeutic cargo (for example, siRNA) and proteins and nucleic acids (for example, microRNA) derived from the donor cell. h | Spherical nucleic acid nanoparticle consisting of a gold core coated in densely packed ASOs attached by metal–thiol linkages. i | Self-assembled DNA cage tetrahedron nanostructure. Oligonucleotide therapeutics (for example, siRNAs and ASOs) 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. LAMP2, lysosome-associated membrane protein 2; Pip, PMO/peptide nucleic acid internalization peptide. Part d shows a schematic of the PSMA (prostate-specific membrane antigen) aptamer adapted from ref.¹⁶⁸, Springer Nature Limited.