This study demonstrates the potential of using programmable editors equipped with transcriptional repressors for the treatment of human diseases by achieving durable and efficient gene silencing in vivo. The researchers targeted the *Pcsk9* gene, which is involved in cholesterol homeostasis, in mouse hepatocytes. They found that zinc-finger proteins were the most effective DNA-binding platform for efficient silencing of *Pcsk9*. A single administration of lipid nanoparticles loaded with the editors' mRNAs almost halved the circulating levels of PCSK9 for nearly one year in mice. Notably, *Pcsk9* silencing and accompanying epigenetic repressive marks persisted even after forced liver regeneration, confirming the heritability of the newly installed epigenetic state. The researchers also developed an all-in-one configuration called evolved engineered transcriptional repressor (EvoETR), which further reduced PCSK9 levels in mice with comparable efficiency to conventional gene editing but without causing DNA breaks. This study lays the foundation for the development of in vivo therapeutics based on epigenetic silencing.This study demonstrates the potential of using programmable editors equipped with transcriptional repressors for the treatment of human diseases by achieving durable and efficient gene silencing in vivo. The researchers targeted the *Pcsk9* gene, which is involved in cholesterol homeostasis, in mouse hepatocytes. They found that zinc-finger proteins were the most effective DNA-binding platform for efficient silencing of *Pcsk9*. A single administration of lipid nanoparticles loaded with the editors' mRNAs almost halved the circulating levels of PCSK9 for nearly one year in mice. Notably, *Pcsk9* silencing and accompanying epigenetic repressive marks persisted even after forced liver regeneration, confirming the heritability of the newly installed epigenetic state. The researchers also developed an all-in-one configuration called evolved engineered transcriptional repressor (EvoETR), which further reduced PCSK9 levels in mice with comparable efficiency to conventional gene editing but without causing DNA breaks. This study lays the foundation for the development of in vivo therapeutics based on epigenetic silencing.