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

Abstract

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.

Nanomaterials-Based Tumor Microenvironment Modulation for Magnifying Sonodynamic Therapy

“…Also, this genome editing technology can be extended to alter heat-resistant genes (e.g., TXNDC5), sensitizing tumor cells to thermal ablation and eventually broadening ablation volume using the corresponding CRISPR/Cas9 delivery system (Figure 5n). 45 Additionally, other ROS-sensitive agents, e.g., X chromosome-linked inhibitor of apoptosis (XIAP) that controls the ROS levels, 46 are also expected to be genetically engineered for enhancing SDT.…”

“…Cancer resistance to ROS therapy rooted in the resistant gene mutation which determines gene therapy is the optimal option in order to fundamentally address the resistance. Gene editing as one of the optimized gene therapies using the cluster regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein (Cas) system is the ideal candidate, where the CRISPR motifs contain specific sequences (spacer regions) separated by identical repetitive sequences. , The CRISPR/Cas delivery system that is envisioned to edit the TME-related genes has profound implications, which paves a solid foundation to genetically alter the cancer resistance and magnify ROS-based antitumor therapy.…”

“…Also, this genome editing technology can be extended to alter heat-resistant genes ( e.g. , TXNDC5), sensitizing tumor cells to thermal ablation and eventually broadening ablation volume using the corresponding CRISPR/Cas9 delivery system (Figure n) . Additionally, other ROS-sensitive agents, e.g.…”

“…(n) Schematic illustration of the design and action mechanism of NIR-II laser mediated delivery of CRISPR/Cas9 system for PTT. Reproduced with permission from ref . Copyright 2021 Wiley-VCH.…”

Stimuli-responsive nanoformulations for CRISPR-Cas9 genome editing

“…Plk-1 was overexpressed in tumor cells, disruption of which can lead to tumor apoptosis. Yin et al [ 196 ] loaded Cas9/sgRNA onto the surface of PEI-decorated silicene nanosheets by physical adsorption and π-stacking, and obtained a silicene-Cas9 gene-editing nanosystem. Silicene is an emerging 2D allotrope of silicon with efficient photothermal-conversion efficiency, high drug-loading capacity, and desirable biocompatibility and biodegradability.…”