Significance: Nucleic acids such as gene-encoding DNAs, gene-silencing small interfering RNAs, or recombinant proteins addressing intracellular molecular targets present a major new therapeutic modality, provided efficient solutions for intracellular delivery can be found. The different physiological redox environments inside and outside the cell can be utilized for optimizing the involved transport processes.
Recent advances: Intracellular delivery of nucleic acids or proteins requires dynamic carriers that discriminate between different cellular locations. Bioreducible cationic polymers can package their therapeutic cargo stably in the extracellular environment, but sense the reducing intracellular cytosolic environment. Based on disulfide cleavage, carriers are degraded into biocompatible fragments and release the cargo in functional form. Disulfide linkages between oligocations, between the carrier and the cargo, or spatial caging of complexed cargo by disulfides have been pursued, with polymers or precise sequence-defined peptides and oligomers.
Critical issues: A quantitative knowledge of the bioreductive capacities within different biological compartments and the involved cellular reduction processes would be greatly helpful for improved carriers with disulfides cleaved within the right compartment at the right time.
Future directions: Novel designs of multifunctional nanocarriers will incorporate macromolecular disulfide entry mechanisms previously optimized by natural evolution of toxins and viruses. In addition to extracellular stabilization and intracellular disassembly, tuned disulfides will contribute to deshielding at the cell surface, or translocation from intracellular compartments to the cytosol.