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A MXene-derived redox homeostasis regulator perturbs the Nrf2 antioxidant program for reinforced sonodynamic therapy.

ABSTRACT: Ultrasound (US)-mediated sonodynamic therapy (SDT) has emerged as a spatiotemporally controllable therapeutic modality in combating cancer because of its high tissue-penetration depth and minimal invasiveness. However, the elevated nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant program in cancer cells can serve as a chief reactive oxygen species (ROS) detoxification system to alleviate oxidative injury and promote tumorigenesis, and thus greatly antagonize the therapeutic efficacy of ROS-mediated anticancer therapies. Herein, we report that vanadium carbide MXene-derived carbon dots (PMQDs) can act as high-efficacy sonosensitizers to efficiently generate ROS upon US irradiation and simultaneously hinder the Nrf2 antioxidant program for enhanced sonodynamic therapy of cancer. These PMQDs show superior US-triggered ROS generating ability because of their efficient migration/separation of electron-hole pairs and narrow bandgap. Importantly, these PMQDs can serve as efficient redox homeostasis regulators to perturb the Nrf2 antioxidant mechanism and thus reduce its effects on ROS neutralization for enhanced SDT efficacy. Overall, the present study will not only provide a new paradigm to augment SDT by perturbing the Nrf2 antioxidant program, but also give valuable insights into developing high-efficacy MXene-derived nanoagents for cancer therapy.

SUBMITTER: Wang H

PROVIDER: S-EPMC9172572 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundColorectal cancer is known to be resistant to immune checkpoint blockade (ICB) therapy. Sonodynamic therapy (SDT) has been reported to improve the efficacy of immunotherapy by inducing immunogenic cell death (ICD) of cancer. However, the SDT efficacy is extremely limited by Nrf2-based natural redox balance regulation pathway in cancer cells in response to the increased contents of reactive oxygen species (ROS). Nuclear-targeting strategy has shown unique advantages in tumor therapy by directly destroying the DNA. Thus it can be seen that Nrf2-siRNA augmented nuclear-targeting SDT could boost ICB therapy against colorectal cancer.ResultsThe nuclear-targeting delivery system TIR@siRNA (TIR was the abbreviation of assembled TAT-IR780) with great gene carrier capacity and smaller diameter (< 60 nm) was designed to achieve the gene augmented nuclear-targeting SDT facilitating the anti-PD-L1 (programmed cell death-ligand-1) therapy against colorectal cancer. In CT26 cells, TIR@siRNA successfully delivered IR780 (the fluorescent dye used as sonosensitizer) into cell nucleus and Nrf2-siRNA into cytoplasm. Under US (utrasound) irradiation, TIR@siRNA notably increased the cytotoxicity and apoptosis-inducing activity of SDT through down-regulating the Nrf2, directly damaging the DNA, activating mitochondrial apoptotic pathway while remarkably inducing ICD of CT26 cells. In CT26 tumor-bearing mice, TIR@siRNA mediated gene enhanced nuclear-targeting SDT greatly inhibited tumor growth, noticeably increased the T cell infiltration and boosted DPPA-1 peptide-based anti-PD-L1 therapy to ablate the primary CT26 tumors and suppress the intestinal metastases.ConclusionsAll results demonstrate that TIR@siRNA under US irradiation can efficiently inhibit the tumor progression toward colorectal CT26 cancer in vitro and in vivo by its mediated gene augmented nuclear-targeting sonodynamic therapy. Through fully relieving the immunosuppressive microenvironment of colorectal cancer by this treatment, this nanoplatform provides a new synergistic strategy for enhancing the anti-PD-L1 therapy to ablate colorectal cancer and inhibit its metastasis.

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A MXene-derived redox homeostasis regulator perturbs the Nrf2 antioxidant program for reinforced sonodynamic therapy.

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