Ultrasound-Controlled CRISPR/Cas9 System Augments Sonodynamic Therapy of Hepatocellular Carcinoma

Abstract Background The combination of sonodynamic therapy and oxygenation strategy is widely used in cancer treatment. However, due to the complexity, heterogeneity and irreversible hypoxic environment produced by Hepatocellular carcinoma (HCC) tissues, oxygen-enhancing sonodynamic therapy (SDT) have failed to achieve the desired results. With the emergence of ferroptosis with reactive oxygen species (ROS) cytotoxicity, this novel cell death method has attracted widespread attention. Methods In this study, nanobubbles (NBs) were connected with the sonosensitizer Indocyanine green (ICG) to construct a 2-in-1 nanoplatform loaded with RAS-selective lethal (RSL3, ferroptosis promoter) (RSL3@O2-ICG NBs), combined with oxygen-enhanced SDT and potent ferroptosis. In addition, nanobubbles (NBs) combined with low-frequency ultrasound (LFUS) are called ultrasound-targeted nanobubble destruction (UTND) to ensure specific drug release and improve safety. Results MDA/GSH and other related experimental results show that RSL3@O2-ICG NBs can enhance SDT and ferroptosis. Through RNA sequencing (RNA-seq), the differential expression of LncRNA and mRNA before and after synergistic treatment was identified, and then GO and KEGG pathways were used to enrich and analyze target genes and pathways related ferroptosis sensitivity. Then we searched for the expression of differentially expressed genes in the TCGA Hepatocellular carcinoma cohort. At the same time, we evaluated the proportion of immune cell infiltration and the identification of co-expression network modules and related prognostic analysis. We found that it was significantly related to the tumor microenvironment of hepatocellular carcinoma. The prognostic risk genes "SLC37A2" and "ITGB7" may represent new hepatocellular carcinoma ferroptosis-inducing markers and have guiding significance for treating hepatocellular carcinoma. Conclusions The therapeutic effect of the in vitro synergistic treatment has been proven to be significant, revealing the prospect of 2-in-1 nanobubbles combined with SDT and ferroptosis in treating HCC.

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Single-cell RNA sequencing reveals the mechanism of sonodynamic therapy combined with a RAS inhibitor in the setting of hepatocellular carcinoma

Journal of Nanobiotechnology ◽

10.1186/s12951-021-00923-3 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Bolin Wu ◽

Yanchi Yuan ◽

Jiayin Liu ◽

Haitao Shang ◽

Jing Dong ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Single Cell ◽

Differentially Expressed Genes ◽

Therapeutic Strategy ◽

Single Cell Analysis ◽

Enrichment Analysis ◽

Differentially Expressed ◽

Cellular Heterogeneity ◽

Sonodynamic Therapy ◽

Frequent Event

Abstract Background Ras activation is a frequent event in hepatocellular carcinoma (HCC). Combining a RAS inhibitor with traditional clinical therapeutics might be hampered by a variety of side effects, thus hindering further clinical translation. Herein, we report on integrating an IR820 nanocapsule-augmented sonodynamic therapy (SDT) with the RAS inhibitor farnesyl-thiosalicylic acid (FTS). Using cellular and tumor models, we demonstrate that combined nanocapsule-augmented SDT with FTS induces an anti-tumor effect, which not only inhibits tumor progression, and enables fluorescence imaging. To dissect the mechanism of a combined tumoricidal therapeutic strategy, we investigated the scRNA-seq transcriptional profiles of an HCC xenograft following treatment. Results Integrative single-cell analysis identified several clusters that defined many corresponding differentially expressed genes, which provided a global view of cellular heterogeneity in HCC after combined SDT/FTS treatment. We conclude that the combination treatment suppressed HCC, and did so by inhibiting endothelial cells and a modulated immunity. Moreover, hepatic stellate secretes hepatocyte growth factor, which plays a key role in treating SDT combined FTS. By contrast, enrichment analysis estimated the functional roles of differentially expressed genes. The Gene Ontology terms “cadherin binding” and “cell adhesion molecule binding” and KEGG pathway “pathway in cancer” were significantly enriched by differentially expressed genes after combined SDT/FTS therapy. Conclusions Thus, some undefined mechanisms were revealed by scRNA-seq analysis. This report provides a novel proof-of-concept for combinatorial HCC-targeted therapeutics that is based on a non-invasive anti-tumor therapeutic strategy and a RAS inhibitor.

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Silica-Based Nanoframeworks Involved Hepatocellular Carcinoma Theranostic

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2021.733792 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yunxi Liu ◽

Yue Chen ◽

Weidong Fei ◽

Caihong Zheng ◽

Yongquan Zheng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Drug Delivery ◽

Photoacoustic Imaging ◽

Fluorescent Imaging ◽

Research Progress ◽

Sonodynamic Therapy ◽

Future Expectations ◽

Advantages And Disadvantages ◽

Positron Emission ◽

Skeleton Structure

Silica-based nanoframeworks have been extensively studied for diagnosing and treating hepatocellular carcinoma (HCC). Several reviews have summarized the advantages and disadvantages of these nanoframeworks and their use as drug-delivery carriers. Encouragingly, these nanoframeworks, especially those with metal elements or small molecular drugs doping into the skeleton structure or modifying onto the surface of nanoparticles, could be multifunctional components participating in HCC diagnosis and treatment rather than functioning only as drug-delivery carriers. Therefore, in this work, we described the research progress of silica-based nanoframeworks involved in HCC diagnosis (plasma biomarker detection, magnetic resonance imaging, positron emission tomography, photoacoustic imaging, fluorescent imaging, ultrasonography, etc.) and treatment (chemotherapy, ferroptotic therapy, radiotherapy, phototherapy, sonodynamic therapy, immunotherapy, etc.) to clarify their roles in HCC theranostics. Further, the future expectations and challenges associated with silica-based nanoframeworks were highlighted. We believe that this review will provide a comprehensive understanding for researchers to design novel, functional silica-based nanoframeworks that can effectively overcome HCC.

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