GA-Chol（glutamate-cholesterol）

GA-Chol（glutamate-cholesterol） is a novel synthetic cholesterol derivative designed to overcome the liver tropism of conventional lipid nanoparticles (LNPs) after local administration. It is synthesized through a two-step reaction involving the covalent conjugation of glutamic acid to cholesterol. When incorporated into LNPs, GA-Chol replaces native cholesterol (typically 38.5 mol%), significantly altering the nanoparticles' properties. A key characteristic of GA-Chol LNPs is their strongly negative zeta potential, which contrasts with the nearly neutral charge of standard cholesterol-containing LNPs. This modification is crucial for altering the LNP's behavior in vivo. Following intramuscular or intratumoral injection, GA-Chol LNPs exhibit superior retention at the injection site, demonstrating robust localized transfection with minimal leakage into the systemic circulation and subsequent off-target expression in the liver. This localized retention effect is consistent across various cancer models. Furthermore, GA-Chol enhances in vitrotransfection efficiency by approximately 10 to 20-fold in different cell lines. Therapeutically, LNPs formulated with GA-Chol enable effective local delivery of potent mRNA cargoes, such as constitutively active caspase-3, achieving significant tumor growth inhibition in mouse models while mitigating risks of hepatotoxicity, showcasing its potential for targeted nucleic acid therapies.