Intelligent Nano‐Cage for Precision Delivery of CRISPR‐Cas9 and ACC Inhibitors to Enhance Antitumor Cascade Therapy Through Lipid Metabolism Disruption

Abstract Reprogramming in lipid metabolism is a hallmark of cancer, and targeting the pivotal enzyme in fatty acid synthesis, acetyl‐CoA carboxylase 1 (ACC1), presents a promising therapeutic strategy. Herein, a nano‐cage encapsulated is constructed by peptide‐modified erythrocyte membrane (NTA630‐NCs‐RBCM‐T) for delivering CRISPR‐Cas9 and ACC1 inhibitors to enable dual‐layer inhibition of ACC1, thereby optimizing the effectiveness of antitumor cascade therapy. NTA630‐NCs‐RBCM‐T are efficiently delivered to cancer cells via peptide‐mediated targeting, releasing Cas9 complexes and ND630 in response to lysosomal enzymes, proton sponge effects, and elevated glutathione levels. The concurrent inhibition of fatty acid synthesis pathways, achieved by Cas9‐mediated ubiquitin‐specific protease 22 (USP22) knockdown and direct inhibition by ND630, enhances polyunsaturated fatty acids (PUFAs) uptake, triggers lipid peroxidation, leading to tumor cell death, particularly ferroptosis, and apoptosis, resulting in effective anti‐tumor activity.