Tryptophan intercalation in siRNA drives the formation of polymeric micelles with enhanced delivery efficiency†

Abstract

The construction of effective carrier systems is essential for delivering therapeutic small interfering RNA (siRNA). In this study, we present an innovative approach using tryptophan intercalation with siRNA to drive the formation of polymeric micelles. Through a facile yet robust method, the siRNA molecules are encapsulated within polymeric micelles formed by flexible poly(ethylene glycol)-poly(glycerol) (PEG-PG) block copolymers bearing biocompatible tryptophane units (PEG-PGTrp). Molecular dynamics (MD) simulations indicated the significance of the indole group, demonstrating its crucial role in fostering favorable interactions through π–π stacking. Moreover, the tryptophan moieties not only aid in the formation of stable micelles, but also contributed to intracellular trafficking and endosomal escape, thereby augmenting siRNA delivery. In vitro studies showed that the PEG-PGTrp-based micelles promoted intracellular delivery of siRNA, leading to enhanced gene knockdown.