Gambogic acid

Photothermal therapy (PTT) offers a promising noninvasive approach for tumor ablation, yet conventional high-temperature PTT (> 50 °C) risks collateral damage to healthy tissues. Mild photothermal therapy (MPTT, ≤ 45 °C) provides a safer alternative but is often undermined by limited efficacy due to heat shock protein (HSP)-mediated thermoresistance. To overcome the barriers, we designed a multifunctional nanoplatform- BQ1-GA nanoparticles (NPs)-by co-encapsulating BQ1, a near-infrared (NIR) organic photothermal agent with high photothermal conversion efficiency (59.2 %), and gambogic acid (GA), a natural HSP90 inhibitor, within a DSPE-PEG₂₀₀₀ matrix. Under 808 nm laser irradiation at a lower power density of 0.5 W/cm², BQ1-GA NPs orchestrate MPTT, HSP90 inhibition, immunogenic cell death (ICD), ferroptosis and apoptosis to enhance the overall antitumor efficacy. More importantly, MPTT triggers ferroptosis and ICD, and ferroptosis in turn enhances immune activation and MPTT efficacy, creating a self-amplifying "MPTT-ICD-ferroptosis" loop. Simultaneously, HSP90 inhibition causes reactive oxygen species (ROS) and lipid peroxide (LPO) buildup, which disrupts HSP90 and augments MPTT, forming a reciprocal amplification "HSP inhibition-MPTT-LPO" cycle. In vivo MPTT in 4T1 tumor-bearing mice, a safer dose of GA (0.26 µg) delivered by BQ1-GA nanoparticles (500 µM, 200 µL) revealed pronounced tumor suppression, durable therapeutic benefits, and minimal off-target toxicity. Collectively, BQ1-GA NPs represent a rationally engineered nanoplatform that integrates HSP90 inhibition, ICD activation, ferroptosis induction and apoptosis to potentiate MPTT, offering a novel and synergistic "1 + 1 > 2" strategy for clinical tumor photothermal therapy.