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

Abstract

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.

Keywords: Ferroptosis; Janus nanoparticles; Leukocyte immunoglobulin-like receptor (LILRB4); Targeted drug delivery; non-small cell lung cancer (NSCLC).