Mutually Synergistic Nanoparticles for Effective Thermo‐Molecularly Targeted Therapy

Abstract Photothermal therapy (PTT) is of particular importance as a highly potent therapeutic modality in cancer therapy. However, a critical challenge still remains in the exploration of highly effective strategy to maximize the PTT efficiency due to tumor thermoresistance and thus frequent tumor recurrence. Here, a rational fabrication of the micelles that can achieve mutual synergy of PTT and molecularly targeted therapy (MTT) for tumor ablation is reported. The micelles generate both distinct photothermal effect from Cypate through enhanced photothermal conversion efficiency and pH‐dependent drug release. The micelles further exhibit effective cytoplasmic translocation of 17‐allylamino‐17‐demethoxygeldanamycin (17AAG) through reactive oxygen species mediated lysosomal disruption caused by Cypate under irradiation. Translocated 17AAG specifically bind with heat shock protein 90 (HSP90), thereby inhibiting antiapoptotic p‐ERK1/2 proteins for producing preferable MTT efficiency through early apoptosis. Meanwhile, translocated 17AAG molecules further block stressfully overexpressed HSP90 under irradiation and thus inhibit the overexpression of p‐Akt for achieving the reduced thermoresistance of tumor cells, thus promoting the PTT efficiency through boosting both early and late apoptosis of Cypate. Moreover, the micelles possess enhanced resistance to photobleaching, preferable cellular uptake, and effective tumor accumulation, thus facilitating mutually synergistic PTT/MTT treatments with tumor ablation. These findings represent a general approach for potent cancer therapy.