A combinatorial synthetic strategy for developing genome-editing protein-delivery agents targeting mouse retina
- Jianye Zhang
- Rafał Hołubowicz
- Roman Smidak
- Yulun Hu
- Samuel W. Du
- Jiin H. Felgner
- Grazyna Palczewska
- Carolline Rodrigues Menezes
- Eleonora Risaliti
- Zhiqian Dong
- Xiuli Ma
- Mojtaba H. Shayegan
- Paul Z. Chen
- Li Xing
- Maria Hołubowicz
- Bowen Li
- David R. Liu
- Philip L. Felgner
- Gregory P. Tochtrop
- Krzysztof Palczewski
2026-02-07
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.