Inflammation-specific DNA origami nanodevice for delivery of siRNAs to treat ulcerative colitis

Small interfering RNAs (siRNAs) have emerged as versatile therapeutic agents for ulcerative colitis, and approaches to optimize their assembly, delivery, and on-demand release are therefore needed. Here, we present a method for the precise assembly and accurate dosing of two types of siRNAs on an enzyme-triggerable DNA origami nanodevice. We design a DNA duplex structure as an inflammation-responsive switch and demonstrate that the nanodevice accumulates autonomously and predominantly in the intestine and selectively exposes siRNAs through a translocated enzyme in inflammatory cells. We find that this strategy can effectively inhibit multiple pathogenic genes and pathways in inflamed cells, while remaining inert in healthy cells. We show that when administered to mice with DSS-induced colitis, the nanodevice increases survival rates up to 100% and exhibits robust therapeutic efficacy and biosafety. This study demonstrates that the nanodevice can serve as a switchable delivery platform for siRNA specifically targeted to the intestine.