Teplensky MH, Fantham M, Poudel C, Hockings C, Lu M, Guna A, et al. A Highly Porous Metal-Organic Framework System to Deliver Payloads for Gene Knockdown. Chem. (2019),5(11):2926–41.
Summary
Since first reported, RNA interference (RNAi) has become a widely used tool for cellular genetic knockdown. However, RNA instability and susceptibility to enzymatic degradation have prevented its widespread clinical use. Thus, research efforts are seeking methods to protect the fragile RNA payload during delivery. Here, we report the use of a metal-organic framework (MOF) to load, protect, and deliver small interfering ribonucleic acids (siRNAs). We confirmed the protection of MOF-internalized siRNA from enzymatic degradation. Furthermore, through combined encapsulation of siRNA in the MOF with various cofactors (proton sponge, KALA peptide, and NH4Cl), we show that endosomal retention can be evaded and ensure that gene knockdown is efficacious. In vitro studies after siRNA-MOF complexation demonstrated up to 27% consistent knockdown. We use structured illumination microscopy (SIM) to study the complex’s endocytic uptake. Overall, we demonstrate the potential of these highly porous and biodegradable materials to improve the efficacy and efficiency of future gene therapies.