Multifunctional “ball-rod” Janus nanoparticles boosting Fenton reaction for ferroptosis therapy of non-small cell lung cancer

Ferroptosis is a newly found cell death mechanism, which could bypass apoptosis and reverse multidrug resistance of tumors. However, efficient induction of tumor ferroptosis remains a challenge. In this study, multifunctional "ball-rod" Janus nanoparticles (FTG/L&SMD) were constructed for non-small cell lung cancer (NSCLC) ferroptosis treatment. Protected by tannic acid (TA), FTG/L&SMD maintains long-term function in blood circulation, while modification by 2, 3-dimethylmaleic anhydride (DMMA) confers the FTG/L&SMD with pH-responsive charge reversal. Glucose oxidase (GOD) on FTG/L&SMD catalyzes glucose to produce H2O2. Then, iron ion converts H2O2 to highly active hydroxyl radicals (OH•) via Fenton reaction, leading to lethal lipid peroxidation (LPO) accumulation. Meanwhile, TA reduces Fe3+ to Fe2+ to boost Fenton reaction cycle. Sor down-regulated glutathione peroxidase 4 (GPX4) expression in another pathway to induce ferroptosis synergistically. In vitro studies have shown that compared with sorafenib (Sor), FTG/L&SMD not only has more efficient tumor targeting and higher cytotoxicity, but also inhibits tumor migration. In vivo antitumor therapy experiments demonstrate that FTG/L&SMD inhibits tumor growth efficiently, and its toxicity is negligible. In general, FTG/L&SMD can initiate Fenton reaction cycle and reinforced ferroptosis to kill tumor cells, which is a promising anti-tumor nano-drug for NSCLC.