DNA-engineered iron single-atom nanozyme for mRNA-guided dual-pathway modulation in enhanced mild photothermal therapy

Mild photothermal therapy (mild PTT) has emerged as a promising approach for tumor treatment that utilizes low-temperature photothermal effects to eliminate tumor tissue while avoiding thermal damage to the surrounding normal tissues. However, its therapeutic efficacy is often limited by the upregulation of heat shock proteins (HSPs), which endow tumor cells with thermal resistance. We have developed a multifunctional DNA-engineered iron single-atom nanozyme (Fe-N-C@DNA) to enhance mild PTT through a "minimize generation, expedite depletion" dual inhibition strategy. The construct achieves gene silencing <i>via</i> sequence-specific DNA-mRNA binding, effectively halting HSP90 synthesis at its genetic source, while enabling real-time fluorescence monitoring. Simultaneously, upon laser irradiation, the Fe-N-C@DNA exhibits excellent photothermal performance and catalyzes the conversion of intracellular H₂O₂ into hydroxyl radicals (˙OH), which disrupts ATP-dependent chaperone function of HSP90 and further augments gene silencing effects. Moreover, the generated ROS can degrade existing HSP90 by cross-linking with proteins. This coordinated "block-and-destroy" mechanism, combined with the photothermal conversion capability of nanozymes, enables comprehensive suppression of the heat shock response, enhancing the efficacy of mild PTT. This work presents an innovative mRNA-guided strategy to overcome the limitations of mild PTT, paving the way for significant advancements in photothermal cancer therapy.