Correction to: Increased RTN3 phenocopies nonalcoholic fatty liver disease by inhibiting the AMPK-IDH2 pathway.
Abstract:
[This corrects the article DOI: 10.1002/mco2.226.].
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Spatiotemporally controlled Pseudomonas exotoxin transgene system combined with multifunctional nanoparticles for breast cancer antimetastatic therapy.
Abstract:
The tumor microenvironment is a barrier to breast cancer therapy. Cancer-associated fibroblast cells (CAFs) can support tumor proliferation, metastasis, and drug resistance by secreting various cytokines and growth factors. Abnormal angiogenesis provides sufficient nutrients for tumor proliferation. Considering that CAFs express the sigma receptor (which recognizes anisamide, AA), we developed a CAFs and breast cancer cells dual-targeting nano drug delivery system to transport the LightOn gene express system, a spatiotemporal controlled gene expression consisting of a light-sensitive transcription factor and a specific minimal promoter. We adopted RGD (Arg-Gly-Asp) to selectively bind to the αvβ3 integrin on activated vascular endothelial cells and tumor cells. After the LightOn system has reached the tumor site, LightOn gene express system can spatiotemporal controllably express toxic Pseudomonas exotoxin An under blue light irradiation. The LightOn gene express system, combined with multifunctional nanoparticles, achieved high targeting delivery efficiency both in vitro and in vivo. It also displayed strong tumor and CAFs inhibition, anti-angiogenesis ability and anti-metastasis ability, with good safety. Moreover, it improved survival rate, survival time, and lung metastasis rate in a mouse breast cancer model. This study proves the efficacy of combining the LightOn system with targeted multifunctional nanoparticles in tumor and anti-metastatic therapy and provides new insights into tumor microenvironment regulation.
Spatiotemporally controllable diphtherin transgene system and neoantigen immunotherapy.
Abstract:
Individualized immunotherapy has attracted great attention due to its high specificity, effectiveness, and safety. We used an exogenous antigen to label tumor cells with MHC I molecules, which allowed neoantigen-specific T cells to recognize and kill tumor cells. A neoantigen vaccine alone cannot achieve complete tumor clearance due to a tumor immunosuppressive microenvironment. The LightOn system was developed to effectively eliminate tumor cells through the spatiotemporally controllable expression of diphtheria toxin A fragment, leading to antigen release in the tumor region. These antigens stimulated and enhanced immunological function and thus, recruited neoantigen-specific T cells to infiltrate tumor tissue. Using the nanoparticle delivery system, neoantigens produced higher delivery efficiency to lymph nodes and improved tumor targeting ability for tumor cell labelling. Good tumor inhibition and prolonged survival were achieved, while eliciting a strong immune response. The combination of a spatiotemporally controllable transgene system with tumor neoantigen labeling has great potential for tumor immunotherapy.
Light-switchable diphtherin transgene system combined with losartan for triple negtative breast cancer therapy based on nano drug delivery system.
Abstract:
Breast cancer is a common malignancy in women. The abnormally dense collagen network in breast cancer forms a therapeutic barrier that hinders the penetration and anti-tumor effect of drugs. To overcome this hurdle, we adopted a therapeutic strategy to treat breast cancer which combined a light-switchable transgene system and losartan. The light-switchable transgene system could regulate expression of the diphtheria toxin A fragment (DTA) gene with a high on/off ratio under blue light and had great potential for spatiotemporally controllable gene expression. We developed a nanoparticle drug delivery system to achieve tumor microenvironment-responsive and targeted delivery of DTA-encoded plasmids (pDTA) to tumor sites via dual targeting to cluster of differentiation-44 and αvβ3 receptors. In vivo studies indicated that the combination of pDTA and losartan reduce the concentration of collagen type I from 5.9 to 1.9 µg/g and decreased the level of active transforming growth factor-β by 75.0% in tumor tissues. Moreover, deeper tumor penetration was achieved, tumor growth was inhibited, and the survival rate was increased. Our combination strategy provides a novel and practical method for clinical treatment of breast cancer.
A combination of LightOn gene expression system and tumor microenvironment-responsive nanoparticle delivery system for targeted breast cancer therapy.
Abstract:
A light-switchable transgene system called LightOn gene expression system could regulate gene expression with a high on/off ratio under blue light, and have great potential for spatiotemporally controllable gene expression. We developed a nanoparticle drug delivery system (NDDS) to achieve tumor microenvironment-responsive and targeted delivery of diphtheria toxin A (DTA) fragment-encoded plasmids to tumor sites. The expression of DTA was induced by exposure to blue light. Nanoparticles composed of polyethylenimine and vitamin E succinate linked by a disulfide bond, and PEGylated hyaluronic acid modified with RGD peptide, accumulated in tumor tissues and were actively internalized into 4T1 cells via dual targeting to CD44 and αvβ3 receptors. The LightOn gene expression system was able to control target protein expression through regulation of the intensity or duration of blue light exposure. In vitro studies showed that light-induced DTA expression reduced 4T1 cell viability and induced apoptosis. Furthermore, the LightOn gene expression system enabled spatiotemporal control of the expression of DTA in a mouse 4T1 tumor xenograft model, which resulted in excellent antitumor effects, reduced tumor angiogenesis, and no systemic toxicity. The combination of the LightOn gene expression system and NDDS may be an effective strategy for treatment of breast cancer.
