A tumor microenvironment acid-responsive therapy combining fenton chemistry and chemotherapy via TNF pathway for synergistic and safe lung cancer treatment.

Lung cancer is one of the most common malignant tumors, but traditional treatments, particularly chemotherapy, often face significant challenges, including drug resistance and high systemic toxicity. In this study, we developed a novel acid responsive nanoparticle, La₂O₃@PDA/PTX, by combining lanthanum oxide (La₂O₃), polydopamine (PDA), and paclitaxel (PTX). This nanoparticle demonstrated excellent aqueous stability, high biocompatibility, and low toxicity. Benefiting from its structural design, the nanoparticle enables targeted delivery of PTX while simultaneously elevating intracellular reactive oxygen species (ROS) levels, which synergistically exacerbates oxidative stress injury within tumor cells. Mechanistically, La₂O₃@PDA/PTX inhibited tumor growth and induced apoptosis by increasing intracellular ROS, inducing G2/M cell-cycle arrest, and regulating proliferation and apoptosis related proteins, including Ki67, Bcl-2, and Bax. At the signaling level, La₂O₃@PDA/PTX increased NF-κB p65 phosphorylation and modulated TNF/NF-κB associated signaling, accompanied by changes in tumor associated cytokines and T-cell associated immunofluorescence signals. Furthermore, it effectively inhibited the progression of both subcutaneous and metastatic tumors with no significant adverse effects on major organs or peripheral blood parameters, showing great promise for future translational research. Collectively, this work presents an acid responsive therapeutic strategy combining ROS enhancement, chemotherapy, and TNF/NF-κB associated signaling modulation for lung cancer treatment.