Chemical modulation of siRNA lipophilicity for efficient delivery

siRNA holds tremendous promise to knockdown the disease-promoting gene in any cell type that it can be delivered. The biggest challenge facing the clinical translation of siRNA is to overcome the barriers that impede the in vivo delivery. siRNA is a highly hydrophilic macromolecule with poor pharmacological properties. The critical requirement for broadening the systemic siRNA delivery is to confer on siRNA the ‘drug-like’ properties such as the lipophilicity. In comparison with unmodified siRNA, lipophilic siRNA has a better cell-membrane compatibility and permeability. The lipophilic siRNA can also hijack the lipid trafficking pathway and natural drug carrier albumin to achieve an advanced systemic delivery, with properties including the tissue targeting, long circulation half-life, the improved pharmacokinetic profile, bioavailability and in vivo safety. In this review, we summarized the recent progress on lipophilic siRNA development, in particular about the chemical methods to manipulate siRNA lipophilicity. The covalent and noncovalent methodologies, including backbone modification, lipid conjugation, chelation method and others, are discussed. We place particular emphasis on the most clinically advanced method, the lipid siRNA conjugation. The application of lipophilic siRNA on nanoparticle delivery system is also covered.