Reductively Dissociable siRNA‐Polymer Hybrid Nanogels for Efficient Targeted Gene Silencing

A highly efficient approach for target‐specific gene silencing based on a reductively dissociable nanogel incorporating small interfering RNA (siRNA) crosslinked with linear polyethylenimine (LPEI) via disulfide bonds is presented. Thiol‐terminated siRNA at both 3′‐ends is electrostatically complexed with thiol‐grafted LPEI. The prepared siRNA/LPEI complex contains inter‐ and intramolecular linkages, generating a mutually crosslinked siRNA/LPEI nanogel (MCN) that exhibits excellent structural stability against the addition of heparin but is readily disintegrated to biologically active, monomeric siRNA upon exposure to reductive conditions. Accordingly, the highly condensed, stable MCN shows greatly enhanced cellular uptake and gene silencing efficiency compared to the siRNA/LPEI complexes without crosslinks or with only LPEI‐mediated crosslinks.