CRISPR-Cas9 may offer new therapeutics for genetic diseases through gene disruption via nonhomologous end joining (NHEJ) or gene correction via homology-directed repair (HDR). However, clinical transition of CRISPR technology is limited by the lack of safe and efficient delivery systems. Here, we report facilely fabricated pH-responsive polymer nanoparticles capable of safely and efficiently delivering Cas9 ribonucleoprotein alone (termed NHEJ-NP, diameter = 29.4 nm), or together with donor DNA (termed HDR-NP, diameter = 33.3 nm). Moreover, intravenously, intratracheally, and intramuscularly injected NHEJ-NP induced efficient gene editing in mouse liver, lung, and skeletal muscle, respectively. Intramuscularly injected HDR-NP also led to muscle strength recovery in a Duchenne muscular dystrophy mouse model. NHEJ-NP and HDR-NP possess many desirable properties including high payload loading content, small and uniform sizes, high editing efficiency, good biocompatibility, low immunogenicity, and ease of production, storage, and transport, making them great interest for various genome editing applications with clinical potentials. This article is protected by copyright. All rights reserved.
Xie R, Wang X, Wang Y, Ye M, Zhao Y, Yandell BS, Gong S. (2022). pH-Responsive Polymer Nanoparticles for Efficient Delivery of Cas9 Ribonucleoprotein With or Without Donor DNA. Advanced materials (Deerfield Beach, Fla.)