biostudies-literatureUnknown11(39)Gao QThe clinical application of CRISPR-Cas9 remains limited by delivery challenges, particularly for oral administration. Lysine-specific demethylase 1 (<i>Lsd1</i>) plays a key role in colonic inflammation and tumorigenesis. Here, we developed an oral genome-editing platform (TPGS-RNP@LNP), where <i>Lsd1</i>-targeting ribonucleoproteins (RNPs) were encapsulated in mulberry leaf lipid nanoparticles (LNPs) and formulated with d-α-tocopherol polyethylene glycol succinate (TPGS). TPGS reinforced the lipid bilayer of LNPs, enhanced gastrointestinal stability, and facilitated colonic mucus penetration. Upon the galactose receptor-mediated endocytosis of TPGS-RNP@LNPs by macrophages, their fusion with the endosomal membrane and the presence of nuclear localization signals ensured the nuclear deliverScience advanceseadw9275https://www.ebi.ac.uk/biostudies/studies/S-EPMC12466914biostudies-literatureReinforced plant-derived lipid nanoparticles for oral precise epigenome editing in colonic diseases.PMC12466914Zu MMa SZhu ZYang KKundu SCMa YReis RLXu HShi XGao QCao YGao YHan HYang QLiu CXiao BfalseReinforced plant-derived lipid nanoparticles for oral precise epigenome editing in colonic diseases.The clinical application of CRISPR-Cas9 remains limited by delivery challenges, particularly for oral administration. Lysine-specific demethylase 1 (<i>Lsd1</i>) plays a key role in colonic inflammation and tumorigenesis. Here, we developed an oral genome-editing platform (TPGS-RNP@LNP), where <i>Lsd1</i>-targeting ribonucleoproteins (RNPs) were encapsulated in mulberry leaf lipid nanoparticles (LNPs) and formulated with d-α-tocopherol polyethylene glycol succinate (TPGS). TPGS reinforced the lipid bilayer of LNPs, enhanced gastrointestinal stability, and facilitated colonic mucus penetration. Upon the galactose receptor-mediated endocytosis of TPGS-RNP@LNPs by macrophages, their fusion with the endosomal membrane and the presence of nuclear localization signals ensured the nuclear deliver2025-01-01T00:00:00Z2025 Sep2026-06-03T21:23:46.33Z2026-05-01T03:11:08.237ZS-EPMC124669144100457910.1126/sciadv.adw9275