Researchers developed a lipid-like material, called lipidoid, that enables low-dose in vivo gene silencing. This material was tested in mice and nonhuman primates, showing effective gene silencing at doses as low as 0.01 mg/kg in mice and 0.03 mg/kg in primates. The lipidoid formulation was able to silence multiple genes simultaneously, including five hepatic genes, after a single injection. This is the first report of simultaneous silencing of five hepatic targets in vivo. The lipidoid-mediated delivery was more potent than previous siRNA delivery systems, with one compound, C12-200, showing over two orders-of-magnitude higher potency than existing formulations. The lipidoid particles were internalized via macropinocytosis, a process that avoids lysosomal degradation, enhancing gene silencing efficiency. The study also demonstrated that the lipidoid formulation is well-tolerated in mice, with no toxicity observed at 1 mg/kg. The results suggest that lipidoid-based delivery systems could significantly improve the therapeutic potential of RNA interference therapeutics by enabling lower doses and simultaneous targeting of multiple genes. The findings have implications for treating diseases such as viral infections and metabolic disorders, where multiple gene targets are involved. The study highlights the importance of developing safe and effective siRNA delivery vehicles for the advancement of RNAi-based therapies.Researchers developed a lipid-like material, called lipidoid, that enables low-dose in vivo gene silencing. This material was tested in mice and nonhuman primates, showing effective gene silencing at doses as low as 0.01 mg/kg in mice and 0.03 mg/kg in primates. The lipidoid formulation was able to silence multiple genes simultaneously, including five hepatic genes, after a single injection. This is the first report of simultaneous silencing of five hepatic targets in vivo. The lipidoid-mediated delivery was more potent than previous siRNA delivery systems, with one compound, C12-200, showing over two orders-of-magnitude higher potency than existing formulations. The lipidoid particles were internalized via macropinocytosis, a process that avoids lysosomal degradation, enhancing gene silencing efficiency. The study also demonstrated that the lipidoid formulation is well-tolerated in mice, with no toxicity observed at 1 mg/kg. The results suggest that lipidoid-based delivery systems could significantly improve the therapeutic potential of RNA interference therapeutics by enabling lower doses and simultaneous targeting of multiple genes. The findings have implications for treating diseases such as viral infections and metabolic disorders, where multiple gene targets are involved. The study highlights the importance of developing safe and effective siRNA delivery vehicles for the advancement of RNAi-based therapies.