Provoking Disulfidptosis-Enhanced Mitophagy by Manganese-Based Nanoplatform via Regulating Cellular Energy Supply and Redox Homeostasis

Metabolic reprogramming and reinforcing redox defense mechanisms in tumors remains major obstacles to oxidative stress therapies in Non-small cell lung cancer (NSCLC). To address these obstacles, we strategically targeted cystine transporter SLC7A11, which plays a central role in cellular redox homeostasis. Herein, guided by bulk RNA-sequencing (RNA-seq) analysis, we identified that concurrent activation of SLC7A11 and inhibition of glucose transporter GLUT1 synergistically delays NSCLC progression. We introduced an effective strategy to effectively target SLC7A11 and GLUT1 for synergistic chemodynamic therapy (CDT) and disulfidptosis. A RNA-seq-guided nanoplatform was constructed from manganese dioxide (HMnO 2 ) with hollow structures and loaded with GLUT1 inhibitor Bay876 (HMnO 2 @Bay). Upon tumor cell uptake, HMnO 2 continuously generates cytotoxic hydroxyl radicals through Fenton-like reaction and activates the expression of SLC7A11. The Bay876 released from the nanoplatform blocks glucose uptake, downregulates NADPH supplementation, and disrupts the SLC7A11-mediated GSH synthesis antioxidant pathway. This boosts disulfidptosis via increased cystine accumulation while concurrently enhancing CDT through the attenuation of GSH-mediated ROS exhaustion. Additionally, RNA-seq explored changes in the transcriptome of tumor cells treated with HMnO 2 @Bay, revealing that the synergistic therapy of CDT and disulfidptosis promotes mitophagy in tumor cells. Comprehensive in vitro and in vivo evaluations reveal the treatment effectively suppresses tumor growth with minimal systemic toxicity. This study provides a promising NSCLC therapy paradigm to induce disulfidptosis-enhanced mitophagy by simultaneously targeting oxidative and glucose dyshomeostasis. • RNA-seq-guided HMnO 2 @Bay nanoplatform targeted SLC7A11 and GLUT1 for NSCLC therapy. • Nanoplatform exhibited ROS generation and MRI imaging capabilities. • Disruption of redox and metabolic homeostasis amplified oxidative stress, GSH depletion, and mitophagy. • Synergistic CDT–disulfidptosis–mitophagy showed high effect against NSCLC.