Well-defined nanogels have become quite attractive as safe and stable carriers for siRNA delivery. However, to avoid nanoparticle accumulation, they need to provide a stimuli-responsive degradation mechanism that can be activated at the payload's site of action. In this work, the synthetic concept for generating well-defined nanohydrogel particles is extended to incorporate disulfide cross-linkers into a cationic nanonetwork for redox-triggered release of oligonucleotide payload as well as nanoparticle degradation under reductive conditions of the cytoplasm. Therefore, a novel disulfide-modified spermine cross-linker is designed that both allows disassembly of the nanogel as well as removal of cationic charge from residual polymer fragments. The degradation process is monitored by scanning electron microscopy (SEM) and fluorescence correlation spectroscopy (FCS). Moreover, siRNA release is analyzed by agarose gel electrophoresis and a fluorescent RNA detection assay. The results exemplify the versatility of the applied nanogel manufacturing process, which allows alternative stimuli-responsive core cross-linkers to be integrated for triggered oligonucleotide release as well as effective biodegradation for reduced nanotoxicity.

Post-polymerization modification of well-defined precursor polymers is a versatile tool to obtain multifunctional water-soluble polymers that cannot be synthesized by common polymerization techniques. For the first time, 1,1,1,3,3,3-hexafluoroisopropyl methacrylate (HFIPMA) based homo and block copolymers were synthesized via RAFT polymerization to provide precise precursors for the postpolymerization modification of the 1,1,1,3,3,3-hexafluoroisopropyl ester side chains with water-soluble amines (methoxy tri(ethylene glycol) amine, 2-hydroxypropyl amine and 3-(dimethylamino)-1propylamine). Sequential aminolysis using Oregon Green cadaverine first followed by 2-hydroxypropyl amine enables access to dye-labelled poly(2-hydroxypropyl methacrylamide) and aminolysis with 3-(dimethylamino)-1-propylamine provides homo and block co-catiomers that complex pDNA in PBS. To this respect, poly(1,1,1,3,3,3-hexafluoroisopropyl methacrylate)s P(HFIPMA)s as precursor polymers may become an alternative route for the synthesis of multifunctional water-soluble polymers for advanced applications.

Back Cover: The synthetic approach toward degradable cationic nanohydrogel particles for siRNA delivery is extended by introducing disulfide‐modified spermine cross‐linkers. Redox‐triggered release of the nanogel's oligonucleotide payload as well as nanoparticle degradation into its single polymer components can be monitored by various methods under reductive conditions of the cytoplasm. Further details can be found in the article by L. Nuhn,* L. Braun, I. Overhoff, A. Kelsch, D. Schaeffel, K. Koynov, and R. Zentel* on page 2057.