Intracellular Delivery of Glutathione Peroxidase Degrader Induces Ferroptosis In Vivo

Abstract

Ferroptosis is a new form of regulated, nonapoptotic cell death driven by iron-dependent phospholipid peroxidation. Its therapeutic potential is however, greatly limited by the low efficiency of regulating cell ferroptosis in vivo. Herein, we report a PROTAC-based protein degrader that depletes endogenous glutathione peroxidase 4 (GPX4) and induces cancer cell ferroptosis. We demonstrate that a rationally designed GPX4 degrader, dGPX4, can deplete tumor cell GPX4 via proteasomal protein degradation, showing a five-fold enhancement of ferroptosis induction efficiency compared to that of GPX4 inhibition using ML162. Moreover, we show that the intracellular delivery of dGPX4 using biodegradable lipid nanoparticles (

Orthogonal Chemical Activation of Enzyme-Inducible CRISPR/Cas9 for Cell-Selective Genome Editing

“…To overcome these limitations, we formulated eiCRISPR containing 17E-BA or 17E-QP DNAzyme with a new type of LNPs, BAmP-TK-12 that are biodegradable to preferably deliver mRNA into cancer cells (Figure S9a,b). 48,49 BAmP-TK-12-mediated delivery of ei-CRISPR enabled the controlled release of eiCRISPR inside tumor cells by making use of the upregulated cellular ROS that degraded BAmP-TK-12, facilitating the selective activation of eiCRISPR by tumoral NQO1. The formulated BAmP-TK-12/ eiCRISPR nanoparticles were around 100 nm in diameter and positively charged, as measured by dynamic light scattering analysis (Figure S9c,d).…”