Disrupting the Fortress: A Biomimetic Nano-Dual-Sensitizer Remodels Tumor Microenvironment via Dual HIF-1α Inhibition
Xin Zhang1, Zutong Cui1, Wenming Liang1
1Hebei Key Laboratory of Applied Chemistry, Hebei Key Laboratory of Nano-biotechnology, Hebei Key Laboratory of Heavy Metal Deep-Remediation in Water and Resource Reuse, Yanshan University, Qinhuangdao 066004, China.
Abstract:
Phototherapy not only targets tumor cells for destruction but also triggers immunogenic cell death (ICD), thereby activating systemic immunity. Traditional photothermal therapy (PTT), however, damages adjacent normal tissues, and photodynamic therapy (PDT) creates severe hypoxia within tumor tissues, which promotes immune evasion and reduces the effectiveness of immunotherapy. In this study, we developed a biomimetic nanomodulators-cell membrane-coated gambogic acid/indocyanine green micelles loaded with HIF-1α siRNA (CM-IGM/siRNA) to achieve mild photothermal therapy (mPTT), enhance photodynamic therapy (PDT), and modulate the tumor microenvironment (TME). This platform utilizes gambogic acid (GA) to inhibit HSP90 expression and synergizes with HIF-1α siRNA to suppress HIF-1α expression, thereby ameliorating hypoxic and immunosuppressive TME. HSP90 inhibition further reduces tumor cell thermotolerance, enabling effective tumor cell ablation at mild hyperthermia temperatures (42-45 °C) characteristic of mPTT. Furthermore, we found that π-π stacking of GA with indocyanine green (ICG) enhances ICG photostability and boosts reactive oxygen species (ROS) generation. The elevated ROS production significantly improves PDT efficacy and, in combination with mPTT, potentiates the ICD of tumor cells. Overall, this strategy offers a significant advancement in cancer immunotherapy by improving the tumor microenvironment and enhancing immune activation.
