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 8C) 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 HSP90a 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.

Cancer therapeutics based on diverse energy sources

“…For effective photothermal therapy (PTT), several strategies have been carried out such as increasing the photothermal conversion efficiency to generate more heat [18][19][20][21] and reducing the thermal tolerance of cancer by blocking specific genes related to heat and repair. [22][23][24][25][26][27] Many review papers have described the photothermal properties of materials. Thus, we will focus on another strategy in this chapter.…”

“…Thus, we will focus on another strategy in this chapter. 20,26,27 For example, in 2020, Zhang's group reported the combination of hydrogels, black phosphorus (BP), and emetine for the stress granule (SG) inhibition-assisted PTT effect (Fig. 3a).…”

Stimuli-responsive nanoformulations for CRISPR-Cas9 genome editing

“…Rapid proliferation of tumor cells and the dysfunction of blood vessels in tumor lead to a decreased oxygen supply, forming a hypoxic tumor microenvironment [168]. Li et al [169] established hypoxia-responsive gold nanorods (AuNRs)based CRISPR-Cas9 nanocomplex for heat shock protein 90 (Hsp90α) gene knockout (Fig. 10B).…”

“…Design of the hypoxia-responsive CRISPR-Cas9 system to reduce tumor thermal tolerance, and hypoxia-triggered delivery of Cas9-sgHSP90α to the nucleus for gene editing and mild-photothermal therapy carried out with NIR light. Reproduced with permission[169]. C MicroRNA-responsive CRISPR-Cas9 delivery nanoformulations.…”

In situ forming oxygen/ROS-responsive niche-like hydrogel enabling gelation-triggered chemotherapy and inhibition of metastasis

“…Many factors of the hypoxia-relevant pathway have been considered as good candidates for theranostic targets, such as reductase and hypoxia-inducible transcription factor 1 (HIF-1) [ 10 , 11 ]. Thus, several theranostic methods are now vigorously being developed, including hypoxia-specific imaging, bioreductive prodrugs, hypoxia-regulated gene therapy, and HIF-1-targeted cancer therapy [ [12] , [13] , [14] ].…”