Capstan lipid CICL-1(L829)

Lipid CICL-1 s a novel ionizable cationic lipid used for tLNP(targeting antibody LNP) targeting to T cell, with pKa range 6-7, high encapsulation efficiency and high T cell transfection, compared to benchmark ATX-126 and other lipids. Lipid CICL-1 is an ionizable cationic lipid featuring a pentaerythritol core symmetrically esterified with four linear C9 alkyl chains (nonanoate esters) to ensure biodegradability. Its structure incorporates a tertiary amine headgroup (-N(CH₃)₂) linked via a short ethoxy spacer, enabling pH-dependent protonation (pKa ~6-7) for optimal nucleic acid encapsulation and endosomal escape. The tetra-branched architecture promotes a conical molecular shape, enhancing lipid nanoparticle (LNP) fusogenicity and cargo release efficiency. The C9 ester chains balance lipophilicity (cLogD ~11-14) for LNP stability while remaining susceptible to esterase hydrolysis, yielding non-toxic metabolites: nonanoic acid, butyrolactone derivatives, and polar diols for renal clearance. Designed to minimize hepatic accumulation, CICL-1’s ester cleavage sites avoid steric hindrance, enabling rapid biodegradation without generating reactive intermediates. Its structure optimizes transfection efficacy in targeted LNPs by maintaining neutral charge at physiological pH (reducing off-target interactions) while acquiring positive charge in acidic endosomes to disrupt membranes. This molecular design synergizes high nucleic acid payload capacity, low cytotoxicity, and metabolic safety for therapeutic applications.