Selection of GalNAc-Conjugated si<i>Keap1</i> as Disease-Specific Delivery System for Chemotherapy-Induced Liver Injury and Chronic Liver Disease.

Abstract

Chemotherapy-induced liver injury (CILI) is a pressing concern in cancer patients. One promising approach involves activating nuclear factor erythroid 2-related factor 2 (Nrf2) to mitigate CILI. However, selectively activating liver Nrf2 without compromising chemotherapy's efficacy has remained elusive. Herein, two RNAi delivery strategies were explored: lipid nanoparticle (LNP) and <i>N</i>-acetylgalactosamine (GalNAc) delivery systems loaded with siRNA designed to silence Kelch-like-ECH associated protein 1 (Keap1) by aiming for liver-specific Nrf2 activation. Remarkably, si<i>Keap1</i>-LNP exhibited unintended tumor targeting alongside liver effects, thereby potentially promoting tumor progression. Conversely, si<i>Keap1</i>-GalNAc did not compromise chemotherapy efficacy and outperformed the conventional Nrf2 activator, bardoxolone, in mitigating CILI. This study proposes si<i>Keap1</i>-GalNAc as a promising therapeutic avenue for liver injury. Importantly, our study bridges a crucial gap concerning the delivery system for liver targeting but not tumor targeting and underscores the importance of selecting nucleic acid delivery systems tailored to specific diseases, not just to specific organs.