A Photothermal Agent with Multiple Hot Shock Proteins Inhibition for Enhanced Tumor Photothermal Therapy and Intrinsic Apoptosis

Abstract Photothermal therapy (PTT) represents a conventional phototherapeutic strategy for tumors; however, the high‐temperature ablation of tumors by photothermal agents inevitably induces a cascade of heat shock responses (HSRs) in tumor cells. HSRs increase tumor thermal resistance by upregulating the expression of heat shock proteins (HSPs), thereby diminishing the efficacy of PTT. In this work, a BODIPY‐based photothermal agent (PTA) with extracellular signal‐regulated kinase (ERK) pathway inhibitory effects is developed (IMH‐BDP). IMH BDP can inhibit the expression of multiple HSPs by suppressing the ERK pathway, thus enhancing the efficacy of PTT. Concurrently, ERK pathway suppression coupled with thermal stimulation during PTT can effectively induce intrinsic apoptosis in tumor cells, further improving tumor treatment efficiency. After IMH‐BDP is encapsulated into polymer nanoparticles (NPs), the formed IMH‐BDP NPs demonstrated enhanced photothermal conversion efficiency (PCE) through aggregation. The inhibition of multiple HSPs, such as HSP60 and HSP70, by IMH‐BDP NPs greatly reduced tumor thermal resistance, which, in conjunction with apoptosis, achieved nearly complete tumor ablation in tumor‐bearing mice after laser irradiation at a safe power density (0.3 W cm⁻ 2 , 808 nm). This design strategy for a photothermal agent that inhibits multiple heat shock proteins offers broader prospects for future research of PTT.