A Multifunctional Nanoreactor‐Induced Dual Inhibition of HSP70 Strategy for Enhancing Mild Photothermal/Chemodynamic Synergistic Tumor Therapy

Abstract Mild photothermal therapy (PTT) is a spatiotemporally controllable method that utilizes the photothermal effect at relatively low temperatures (40–45 °C) to especially eliminate tumor tissues with negligible side effects on the surrounding normal tissues. However, the overexpression of heat shock protein 70 (HSP70) and limited effect of single treatment drastically impede the therapeutic efficacy. Herein, the constructed multifunctional core‐shell structured Ag‐Cu@SiO 2 ‐PDA/GOx nanoreactors (APG NRs) that provide a dual inhibition of HSP70 strategy for the second near‐infrared photoacoustic (NIR‐II PA) imaging‐guided combined mild PTT/chemodynamic therapy (CDT). The Ag‐Cu cores can convert endogenous H 2 O 2 to hydroxyl radical (•OH), which can induce lipid peroxidation (LPO) and further degrade HSP70. The polydopamine (PDA)/glucose oxidase (GOx) shells are utilized as the NIR‐II photothermal agent to generate low temperature, and the GOx can reduce the energy supplies and inhibit energy‐dependent HSP70 expression. Furthermore, both the generation of •OH and GOx‐mediated energy shortage can reduce HSP70 expression to sensitize mild PTT under 1064 nm laser, and in turn, GOx and laser self‐amplify the catalytic reactions of APG NRs for more production of •OH. The multifunctional nanoreactors will provide more potential possibilities for the clinical employment of mild PTT and the advancement of tumor combination therapies.