Lipid Nanoparticle (LNP) Chemistry Can Endow Unique In Vivo RNA Delivery Fates within the Liver That Alter Therapeutic Outcomes in a Cancer Model

• DOI: 10.1021/acs.molpharmaceut.2c00442
• Publication Date: 2022-09-26T12:01:15Z
• Authors: Lindsay T. Johnson; Di Zhang; Kejin Zhou; Sang M. Lee; Shuai Liu; Sean A. Dilliard; Lukas Farbiak; Sumanta Chatterjee; Yu-Hsuan Lin; Daniel J. Siegwart
• Keywords: Liver Cancer

Within the field of lipid nanoparticles (LNPs) for RNA delivery, focus has been mainly placed on organ level which can mask cellular effects consequential to therapeutic applications. Here, we studied a pair LNPs with similar physical properties and discovered how chemistry ionizable amino control endogenous LNP identity, affecting uptake in liver altering outcomes model cancer. Although most accumulate after intravenous administration (suggesting that delivery is straightforward), observed an unexpected behavior when comparing two formulations (5A2-SC8 3A5-SC14 LNPs) resulted distinct within organ. Despite both possessing properties, ability silence gene expression vitro, strong accumulation liver, shared pKa 6.5, only 5A2-SC8 were able functionally deliver hepatocytes. Factor VII (FVII) activity was reduced by 87%, carrying FVII siRNA (siFVII), while siFVII produced baseline levels comparable nontreatment at dosage 0.5 mg/kg. Protein corona analysis indicated bind apolipoprotein E (ApoE), drive LDL-R receptor-mediated endocytosis In contrast, surface enriched albumin but depleted ApoE, likely led Kupffer cell detargeting aggressive MYC-driven cancer relevant hepatocytes, let-7g miRNA significantly extend survival up 121 days. Since disease targets exist organ- cell-specific manner, clinical development therapeutics will require improved understanding tropism organs. The results from our work illustrate importance localization incorporating further checkpoints choosing beyond biochemical characterization, as small changes chemical composition have impact biofate outcomes.