Extended Data Fig. 1: Mechanism of YOLT-101 in reducing PCSK9 and lowering LDL-C.

a, The structure of YOLT-101, which is administered via intravenous infusion. Its carrier system is a GalNAc-modified lipid nanoparticle (LNP) system, designed for enhanced targeted delivery to hepatocytes. The active components, including adenine base editor (hpABE5) mRNA and single-guide RNA (sgRNA), are encapsulated within the LNP and specifically target the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene in the liver. b, The dual-targeting mechanism by which YOLT-101 is delivered to hepatocytes. Following administration and entry into the circulation, the LNPs are opsonized by apolipoprotein E (ApoE). The LNPs, which contain the active components, bind to the low-density lipoprotein receptor (LDLR) on hepatocyte surfaces via ApoE, facilitating receptor-mediated endocytosis. Simultaneously, the LNPs are directed to hepatocytes through GalNAc, which specifically targets the asialoglycoprotein receptor (ASGPR) on hepatocyte surfaces, enhancing delivery via an LDLR-independent pathway. c, The precise base editing process. Upon entering the hepatocyte, sgRNA guides the hpABE5 ribonucleoprotein complex to the target site in the PCSK9 gene. The complex catalyzes the deamination of adenine (A) to inosine (I), which is then processed by the cell’s DNA repair machinery as guanine (G). This results in a precise A-to-G substitution, disrupting the normal splicing of PCSK9 mRNA and introducing a frameshift mutation that inactivates the PCSK9 gene, effectively silencing its expression. d, The reduction in PCSK9 expression leads to enhanced recycling of the LDLR. With less PCSK9 available to degrade LDLR, the receptors remain functional and are efficiently recycled, increasing LDL-C uptake into hepatocytes. This process lowers circulating LDL-C levels, thereby resulting in the therapeutic effect of YOLT-101.