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.