An Oxidative Stress Nanoamplifier to Enhance the Efficacy of Cisplatin in Head and Neck Cancer

Abstract Cisplatin (CP) is a first‐line platinum‐based drug used for the treatment of head and neck cancer. However, tumor cells can diminish the therapeutic effects of CP through the detoxification system mediated by glutathione (GSH) and the nucleotide excision repair (NER) pathway. Herein, we present a light‐activable and pH‐responsive oxidative stress nanoamplifier (FPLC@IR OSNA), comprising an amphiphilic compound (FPLC) with Fmoc‐lysine acting as a connector between a nitroimidazole derivative and a pH‐responsive cinnamaldehyde (CA) derivative, loaded with photosensitizer IR780. The acidic microenvironment of the lysosome can trigger the release of CA to produce H 2 O 2 , which breaks down into oxygen, further improving the phototherapy efficacy mediated by IR780 irradiation. The consumption of oxygen during the phototherapy process induces hypoxia, prompting the reduction of nitroimidazole to aminoimidazole and leading to reduced GSH synthesis, enhancing tumor cell death induced by CP. Meanwhile, the accumulation of intracellular reactive oxygen species (ROS) during phototherapy attenuates the nuclear NER pathway, further augmenting the therapy effect of CP. This strategy, by combining FPLC@IR OSNA with laser and CP, significantly promotes the therapeutic effect in vitro and notably inhibits tumor growth in both Cal27 cell line‐derived xenograft models and patient‐derived xenograft models.