Hypoxia-Responsive Gene Editing to Reduce Tumor Thermal Tolerance for Mild-Photothermal Therapy.

Near-infrared (NIR)-light-triggered photothermal therapy (PTT) is usually associated with an undesirable heating damage to normal organs nearby due to its high temperature (>50 o C) for available tumor ablation. Achieving PTT strategies at a relatively low temperature therefore demonstrates tremendous value to clinic. Here, we construct a hypoxia-responsive gold nanorods (AuNRs)-based nanocomposite of CRISPR-Cas9 for mild-photothermal therapy via tumor-targeted gene editing. AuNRs are modified with azobenzene-4, 4'-dicarboxylic acid (p-AZO) to achieve on-demand release of CRISPR-Cas9 using hypoxia-responsive azo bonds. In the hypoxic tumor microenvironment, the azo groups of APACPs are selectively reduced by the overexpression of reductases, leading to the release of Cas9 and subsequent gene editing. Owing to the knockout of Hsp90α for reducing thermal-resistance of cancer cells, highly effective tumor ablation both in vitro and in vivo was achieved with APACPs under mild PTT. This strategy provides a promising method for gene editing targeting tumor microenvironments, and opens a possibility to improve the therapeutic effect and minimize the side effects.