Emetine-Loaded Black Phosphorus Hydrogel Sensitizes Tumor to Photothermal Therapy through Inhibition of Stress Granule Formation

During photothermal therapy (PTT), hyperthermia up to 50 °C is required for efficient induction of tumor cell death. Additional increases in temperature can lead to severe damage to adjacent tissues. Conversely, insufficient heating of deep-seated tumor tissues results in tumor recurrence. Sensitization of tumor cells to PTT may solve this problem. Stress granules (SGs) function in integration of various internal and external stresses to regulate cell viability. However, the role of SGs in PTT is currently unknown. Here, with black phosphorus (BP) nanosheets as photothermal agents, it is found that SGs are induced in tumor by PTT through eukaryotic initiation factor 2α-dependent pathway and participate in tumor resistance to PTT. To modulate SG formation in tumor, a BP hydrogel is prepared for tumor-specific delivery and near-infrared (NIR) light-controlled release of the SG inhibitor Emetine. Upon NIR-light irradiation, photothermal conversion of BP nanosheets enables PTT of tumor. Meanwhile, light-controlled release of Emetine in tumor tissues effectively inhibits PTT-induced SG formation and sensitizes tumor to PTT, resulting in enhanced tumor inhibition. These results reveal the role of SGs in PTT and present a novel strategy for tumor sensitization to enhance the therapeutic efficacy and reduce the side effects of PTT.