Polymers present an interesting option for the delivery of genes and other therapeutic nucleic acids. In the delivery process, the polymeric carriers face many different delivery tasks and different physiological microenvironments. Polymers can be designed to respond to microenvironmental differences with changes in their physio-chemical properties, enabling them to perform individual delivery tasks. Cleavage of covalent bonds, disassembly of noncovalent interactions, changes of protonation, conformation, or hydrophilicity/lipophilicity, can trigger such dynamic physicochemical adjustments. The polymeric carrier has to stably bind the therapeutic nucleic acid during the extracellular delivery phase and protect it against degradation in the bloodstream. At the intracellular site of action, the polyplex has to disassemble to an extent that the nucleic acid is functionally accessible. Polyplexes need to be shielded in the circulation and be inert against numerous possible biological interactions, but should actively interact with the target cell surface by electrostatic or ligand receptor interactions. Lipid-membrane destabilization at the cell membrane or nontarget sites is usually associated with undesired cytotoxicity, the analogous biophysical event, however, is required within an endocytic vesicle for polyplex transfer into the cytosol. Strategies will be presented how bioresponsive polymers can be designed and incorporated into polyplexes. Examples include dynamic stabilization of the polymerucleic acid core and transient activation of properties required for crossing lipid-membrane barriers. Bioresponsive delivery domains at the polyplex surface required for shielding, deshielding, and cell targeting also contribute to better performance.
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