A combinatorial synthetic strategy for developing genome-editing protein-delivery agents targeting mouse retina

Jianye Zhang(University of California, Irvine), Rafał Hołubowicz(Wrocław University of Science and Technology), Roman Šmidák(University of California, Irvine), Yulun Hu(Case Western Reserve University), Samuel W. Du(University of California, Irvine), Jiin Felgner(University of California, Irvine), Grażyna Palczewska(University of California, Irvine), Carolline Rodrigues Menezes(University of California, Irvine), Eleonora Risaliti(University of California, Irvine), Zhiqian Dong(University of California, Irvine), Xiuli Ma(University of California, Irvine), Mojtaba H. Shayegan(Case Western Reserve University), Paul Chen(Broad Institute), Li Xing(University of California, Irvine), Maria W. Hołubowicz(University of California, Irvine), Bowen Li(Case Western Reserve University), David R. Liu(Broad Institute), Philip L. Felgner(University of California, Irvine), Gregory P. Tochtrop(Case Western Reserve University), Krzysztof Palczewski(University of California, Irvine)
Nature Communications
February 7, 2026
10.1038/s41467-026-69077-w
Cited by 0Open Access
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Abstract

CRISPR/Cas9-based gene-editing technologies offer promise for treating inherited retinal diseases (IRDs), however safe and efficient ocular delivery of precision editors remains challenging. To address this challenge, we report a class of Coomassie brilliant blue (CBB)-derived lipidoids that bind and deliver proteins. Subretinal injection of Cre complexed with these lipidoids into mT/mG mice leads to robust recombination in the retinal pigment epithelium and photoreceptors. We employ the CBB-lipidoid platform to deliver adenine base editor (ABE) ribonucleoproteins (RNP). Incorporating CBB lipidoids into liposomes improves delivery efficiency. CBB11 stands out for facilitating precise in vivo ABE-mediated gene editing. Delivery of liposome-CBB11-RNP complexes results in a 120-fold increase in base editing compared to RNP alone and restores the scotopic ERG b-wave response in the rd12 mouse model. These results demonstrate the potential of CBB-augmented, liposome-RNP systems for therapeutic gene editing in the eye, paving the way for single-dose precision medicines to treat IRDs.

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