Dual‐Responsive PPy‐AIPH@LA Nanoplatform for Synergistic Photothermal and Thermodynamic Therapy of Colorectal Cancer

Abstract In this study, we introduce a novel nanoplatform, polypyrrole (PPy)‐2,2′‐Azobis[2‐(2‐imidazolin‐2‐yl)propane] dihydrochloride (AIPH)@lauric acid (LA) (PPy‐AIPH@LA) nanoparticles (NPs), designed to overcome these limitations through synergistic photothermal therapy (PTT) and photodynamic therapy (PDT). This dual‐responsive system incorporates PPy for efficient photothermal conversion, AIPH for thermos‐responsive and oxygen‐independent free radical generation, and LA as a thermally responsive encapsulation layer. The LA coating melts upon 808 nm near‐infrared laser irradiation, releasing AIPH and free radicals to enable precise spatiotemporal activation of therapeutic effects. PPy‐AIPH@LA demonstrates exceptional photothermal conversion efficiency (55.74%) and generates sufficient radicals to enhance PDT efficacy, even in hypoxic tumor microenvironments. In vitro studies revealed concentration‐dependent tumor cell ablation and inhibition of migration, while in vivo experiments showed that the combined PTT‐PDT treatment achieved an impressive 90.7% tumor growth inhibition rate in a mouse colon cancer cells CT‐26 murine model, with no significant systemic toxicity. Molecular analyses further revealed modulations in pathways associated with tumor metabolism, apoptosis, and immune escape, highlighting the comprehensive therapeutic potential of this nanoplatform. These findings underscore the potential of PPy‐AIPH@LA as a safe, effective, and minimally invasive nanotherapeutic platform for combating CRC and other solid tumors.