NIR-II conjugated polymer/emodin nanoplatform for mild photothermal therapy/pyroptosis of head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) remains a clinically challenging malignancy due to limited therapeutic options and considerable treatment-related toxicity. In this study, we present an innovative nanotherapeutic platform—monocarboxylate transporter 1 (MCT1) antibody-targeted nanoparticles co-loaded with a second near-infrared window (NIR-II, 1000–1700 nm) absorbing conjugated polymer (PDTP-TBZ-OD, denoted as PTO) and emodin (MCT@PTO-Em NPs) —that synergistically integrates emodin-induced pyroptosis with NIR-II mediated mild photothermal therapy (MPTT) to address critical limitations of current HNSCC treatments strategies. The synthesized NIR-II-absorbing conjugated polymer PTO exhibits strong absorption at 1064 nm and a high photothermal conversion efficiency (39 %), enabling deeptissue penetration and precise hyperthermia control. Accordingly, MCT@PTO-Em NPs implement a dual-modal therapeutic strategy that triggers pyroptosis through NLRP3 inflammasome activation while simultaneously enhancing tumor cell death via mild hyperthermia. Moreover, emodin encapsulated within the nanoparticles (NPs) inhibits heat-shock protein 70 (HSP70), thereby disrupting cellular thermoresistance mechanisms and sensitizing cancer cells to MPTT. Additionally, surface functionalization of the nanoparticles with MCT1-targeting antibodies enhances tumor-specific delivery and intracellular accumulation, thereby minimizing off-target effects. Both in vitro and in vivo studies demonstrate that MCT@PTO-Em NPs achieve superior tumor suppression through the synergistic interplay between pyroptosis and MPTT, while exhibiting excellent biocompatibility. This work presents a precision nanomedicine strategy that integrates molecular targeting, pyroptosis-mediated immune activation, and MPTT, offering a transformative therapeutic paradigm for HNSCC and other solid tumors.