A Triazolium‐Anchored Self‐Immolative Linker Enables Self‐Assembly‐Driven siRNA Binding and Esterase‐Induced Release

The increased importance of RNA‐based therapeutics comes with a need to develop next‐generation stimuli‐responsive systems capable of binding, transporting and releasing RNA oligomers. In this work, we describe triazolium‐based amphiphiles capable of siRNA binding and enzyme‐responsive release of the nucleic acid payload. In aqueous medium, the amphiphile self‐assembles into nanocarriers that can disintegrate upon the addition of esterase. Key to the molecular design is a self‐immolative linker that is anchored to the triazolium moiety and acts as a positively‐charged polar head group. We demonstrate that addition of esterase leads to a degradation cascade of the linker, leaving the neutral triazole compound unable to form complexes and therefore releasing the negatively‐charged siRNA. The reported molecular design and overall approach may have broad utility beyond this proof‐of‐principle study, because the underlying CuAAC “click” chemistry allows bringing together three groups very efficiently as well as cleaving off one of the three groups under the mild action of an esterase enzyme.