A2T2C9 (CP-LC-1465) is an imidazole-based ionizable lipid with branched hydrophobic chains and β-propionate linkers, formulated in four-component LNPs for spleen-targeted mRNA delivery. It achieves >80% spleen selectivity with protein expression exceeding 1×10⁷ p/s in mice, driven by its negative zeta potential (-9.7 to -19 mV). Structural features including imidazole polar head and branched acrylate (C9) enhance splenic tropism, potentially through distinct protein corona interactions. Demonstrated low cytotoxicity (>75% viability in splenic cells) and biodegradability via pH-sensitive linkers enable efficient mRNA delivery without permanent charged additives, outperforming conventional anionic SORT systems in selectivity and therapeutic potential.
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