Multifunctional Nanoparticles Inhibit HSPs Expression and Improve Pyroptosis Through ROS Amplification in Mild Photothermal Therapy of Oral Squamous Cell Carcinoma

Reactive oxygen species (ROS) can catalyze the palmitoylation of Gasdermin D (GSDMD), thereby promoting pyroptosis. However, tumor cells frequently exhibit elevated expression of heat shock proteins (HSPs), which attenuate pyroptosis through the inhibition of key pyroptotic mediators. To solve these problems, a folate‐acid‐modified polydopamine nanoparticle loaded with copper peroxide (PDCF nanoparticles) is developed to simultaneously trigger and amplify pyroptosis while suppressing HSPs‐mediated defensive mechanisms. PDCF nanoparticles efficiently elevated intracellular ROS, thereby directly promoting the palmitoylation and subsequent cleavage of GSDMD to its active N‐terminal GSDMD (GSDMD‐N). This process created a positive feedback loop that enhanced pyroptosis, characterized by pore formation in the plasma membrane and the release of interleukin 1β (IL‐1β) and interleukin 18 (IL‐18). Concurrently, the elevated ROS significantly downregulated HSPs expression to achieve a mild photothermal therapy (MPTT). This combined strategy of pyroptosis amplification and HSPs inhibition potently suppressed tumor growth in oral squamous cell carcinoma (OSCC). The novel multifunctional therapeutic strategy provides a new view for the treatment of OSCC through ROS‐mediated downregulation of HSPs and improving pyroptosis.