GVS-18-B6 is a silicon ether-based ionizable lipid developed by Genevant, optimized for mRNA-LNP delivery, characterized by a short-chain trialkyl structure with three C10 alkyl chains (including a cis double bond) and a dimethylamino (DMA) head group linked via a 4-carbon spacer (pKa ~6.15). Its LNP formulations exhibit a narrow particle size distribution (89 nm, PDI=0.06), high mRNA encapsulation efficiency (90%), and pH-dependent surface charge (−0.11 mV at pH 7.5 vs. +2.69 mV at pH 5.5), facilitating endosomal escape. In vivo, GVS-18-B6 demonstrated superior liver-specific mRNA expression (5.30×10⁷ pg EGFP/g liver, 2.6× higher than MC3) with minimal spleen accumulation (liver/spleen ratio 92:1 vs. MC3’s 10:1), attributed to rapid non-enzymatic hydrolysis of its silicon ether bonds. This mechanism enables near-complete hepatic clearance within 6 hours in mice and 24 hours in NHPs, avoiding long-term organ retention (MC3 retained 25% in liver after 28 days). Compared to benchmarks (MC3, SM-102, LP-01), GVS-18-B6 showed enhanced potency in RBC hemolysis assays (pH 6.2), indicating earlier endosomal membrane disruption, and maintained stability through 12-month frozen storage or repeated freeze-thaw cycles. Toxicity profiling revealed minimal immunogenicity (MCP-1 levels 0.58×10⁶ vs. MC3’s 1.10×10⁶) and no ALT/AST elevation or anti-PEG antibody induction in NHPs after repeated dosing. Its species-agnostic clearance, low off-target effects, and high tolerability (6 mg/kg dose in mice) position GVS-18-B6 as a leading candidate for chronic disease therapies requiring frequent mRNA administration.
