Ultrathin BSA‐Stabilized Black Phosphorous Nanoreactor Boosts Mild‐Temperature Photothermal Therapy Through Modulation of Cellular Self‐Defense Fate

Mild‐temperature photothermal therapy (mild‐PTT, 42–45 °C) offers a higher level of biosafety. However, its therapeutic effects are compromised by the heat shock response (HSR), a cellular self‐defense mechanism, which triggers the overexpression of heat shock proteins (HSPs) with the capacity of repairing the damaged tumor cells. Herein, this work fabricates a novel nanoreactor by incorporating up‐conversion nanoparticles (UCNPs), chlorin e6 (Ce6), and glucose oxidase (GOx) onto the ultrathin black phosphorus nanosheet (BPNS) (denoted as GOx‐BUC). This nanoreactor amplifies mild‐PTT effects under irradiation with an 808 nm laser, modulating HSPs‐mediated cellular self‐defense fate. On one hand, upon irradiation with a 980 nm laser, UCNPs can transfer energy to excite Ce6, leading to the generation of ROS burst, which achieves indiscriminate damage to HSPs activity in deeper tumor tissues. On the other hand, GOx can consume glucose, thereby depleting the ATP energy supply and further suppressing HSPs expression. Consequently, GOx‐BUC exhibits excellent anti‐tumor efficacy under mild temperature in a human colorectal cancer mouse model, resulting in complete tumor inhibition with negligible side effects. This black phosphorous nanoreactor, featuring dual‐track HSPs destruction functionality, introduces novel perspectives for enhancing mild‐PTT effectiveness while maintaining high biosafety.