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 N-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, siKeap1-LNP exhibited unintended tumor
targeting alongside liver effects, thereby potentially promoting tumor
progression. Conversely, siKeap1-GalNAc did not compromise
chemotherapy efficacy and outperformed the conventional Nrf2 activator,
bardoxolone, in mitigating CILI. This study proposes siKeap1-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.