Cell‐Selective siRNA Delivery Using Glycosylated Dynamic Covalent Polymers Self‐Assembled In Situ by RNA Templating

Dynamic covalent libraries enable exploring complex chemical systems from which bioactive assemblies can adaptively emerge through template effects. In this work, we studied dynamic covalent libraries made of complementary bifunctional cationic peptides, yielding a diversity of species from macrocycles to polymers. Although polymers are typically expressed only at high concentration, we found that siRNA acts as a template in the formation of dynamic covalent polymers at low concentration in a process guided by electrostatic binding. Using a glycosylated building block, we were able to show that this templated polymerization further translates into the multivalent presentation of carbohydrate ligands, which subsequently promotes cell uptake and even cell‐selective siRNA delivery. Dynamic covalent polymers are expressed at low concentration by siRNA templating from peptide‐based dynamic covalent libraries. Using a glycosylated building block, we show that this templated polymerization further translates into the multivalent presentation of carbohydrate ligands, which subsequently promotes cell uptake and even cell‐selective siRNA delivery.