CRISPR/Cas9‐2D Silicene Gene‐Editing Nanosystem for Remote NIR‐II‐Induced Tumor Microenvironment Reprogramming and Augmented Photonic Tumor Ablation

Photothermal therapy (PTT) is a minimally invasive and highly specific antineoplastic treatment, whereas the significant upregulation of TXNDC5 gene expression following PTT cripples the photothermal ablation efficacy through protein processing in the endoplasmic reticulum signaling pathway, as transcriptome sequencing and bioinformatics analysis revealed in this research. To tackle this crucial issue, a second near‐infrared biowindow (NIR‐II) light‐controlled CRISPR/Cas9 nanosystem (silicene‐Cas9) is constructed based on biosafe and biodegradable 2D silicene nanosheets with desirable photothermal‐conversion capability. The elaborate system enables remote NIR‐II‐induced reprogramming of tumor microenvironment for enhanced photonic tumor ablation. Moreover, this CRISPR/Cas9 delivery system is carried out to precisely and efficiently knock down TXNDC5 for reprogramming the tumor microenvironment and amplifying the photothermal performance of silicene, exhibiting high efficiency and controlled gene‐editing capacity of 47.68% and significantly improving therapeutic effect of tumor ablation without recurrence both in vitro and in vivo. This work not only provides a paradigm of improving the effectiveness of photothermal tumor therapy, but also develops a safe and efficient 2D silicene‐based nonviral vector for harnessing CRISPSR/Cas9 technology‐mediated genome editing, which further broadens the biomedical application of 2D silicene nanosheets. Herein, a second near‐infrared biowindow (NIR‐II) light‐controlled CRISPR/Cas9 nanosystem, termed as silicene‐Cas9, is constructed based on biosafe and biodegradable 2D silicene nanosheets. This work not only elucidates/addresses the underlying therapeutic efficacy challenge of photothermal tumor ablation, but also explores a gene‐editing synergistic therapy modality based on a novel CRISPR/Cas9 gene delivery system, which also further broadens the biomedical application of 2D silicene nanosheets.