Poly(beta-amino ester)-Based Nanoparticles Enable Nonviral Delivery of Base Editors for Targeted Tumor Gene Editing

Base editing is an emerging genome editing technology with the advantages of precise base corrections, nodouble-strand DNA breaks, and no need for templates, whichprovides an alternative treatment option for tumors with pointmutations. However, effective nonviral delivery systems for baseeditors (BEs) are still limited. Herein, a series of poly(beta-aminoesters) (PBAEs) with varying backbones, side chains, and end capswere synthesized to deliver plasmids of BEs and sgRNA. Efficienttransfection and base editing were achieved in HEK-293T-sEGFPand U87-MG-sEGFP reporter cell lines by using lead PBAEs,which were superior to PEI and lipo3k. A single intratumor injection of PBAE/pDNA nanoparticles induced the robust conversionof stopped-EGFP into EGFP in mice bearing xenograft glioma tumors, indicating successful gene editing by ABEmax-NG. Overall,these results demonstrated that PBAEs can efficiently deliver BEs for tumor gene editing both in vitro and in vivo