This study presents a novel formulation of lipid-like materials, specifically C12-200, for the delivery of small interfering RNAs (siRNAs) to liver cells. The formulation enables siRNA-directed liver gene silencing in mice at doses as low as 0.01 mg/kg, significantly lower than previously reported systems. The formulation was also shown to simultaneously silence five hepatic genes after a single injection. In nonhuman primates, high levels of knockdown of the clinically relevant gene transthyretin were observed at doses as low as 0.13 mg/kg. The study highlights the potential of this formulation to reduce the dosage of siRNA and formulation materials, thereby improving tolerability and therapeutic potential. The mechanism of cellular uptake by C12-200 particles was investigated, suggesting that they may be internalized through macropinocytosis. The results demonstrate the feasibility of using this formulation for multitargeted gene silencing, which could be particularly useful in treating diseases with multiple gene targets.This study presents a novel formulation of lipid-like materials, specifically C12-200, for the delivery of small interfering RNAs (siRNAs) to liver cells. The formulation enables siRNA-directed liver gene silencing in mice at doses as low as 0.01 mg/kg, significantly lower than previously reported systems. The formulation was also shown to simultaneously silence five hepatic genes after a single injection. In nonhuman primates, high levels of knockdown of the clinically relevant gene transthyretin were observed at doses as low as 0.13 mg/kg. The study highlights the potential of this formulation to reduce the dosage of siRNA and formulation materials, thereby improving tolerability and therapeutic potential. The mechanism of cellular uptake by C12-200 particles was investigated, suggesting that they may be internalized through macropinocytosis. The results demonstrate the feasibility of using this formulation for multitargeted gene silencing, which could be particularly useful in treating diseases with multiple gene targets.