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

Abstract Near‐infrared (NIR)‐light‐triggered photothermal therapy (PTT) is usually associated with undesirable damage to healthy organs nearby due to the high temperatures (>50 °C) available for tumor ablation. Low‐temperature PTT would therefore have tremendous value for clinical application. 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 the hypoxia‐activated CRISPR‐Cas9 nanosystem based on gold nanorods (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 the thermal resistance of cancer cells, highly effective tumor ablation both in vitro and in vivo was achieved with APACPs under mild PTT.