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An increasing body of evidence suggests that acylphosphatase-2 (ACYP2) polymorphisms are correlated with an increased susceptibility to a range of malignancies. Nevertheless, its potential functions, molecular mechanisms in hepatocellular carcinoma (HCC) and whether it can be act as a therapeutic target remain uninvestigated. Herein, ACYP2 was found to be lowly expressed in HCC and was negatively correlated with tumor size, tumor differentiation, microvascular invasion and the prognosis of HCC patients. Functional investigations revealed that overexpression of ACYP2 inhibited the proliferation and metastasis of HCC cells while promoting apoptosis; knockdown of ACYP2 had the exact opposite effect. Additionally, it was observed that ACYP2 was distributed in both the cytoplasm and nucleus of HCC cells. According to the mechanistic studies, the expression of potassium calcium-activated channel subfamily N member 4 (KCNN4) was negatively regulated by cytoplasmic ACYP2, resulting in the inhibition of K + outflow and subsequent inactivation of the ERK pathway, which impeded the growth and metastasis of HCC. Furthermore, the activity of telomerase reverse transcriptase (TERT) was inhibited by nuclear ACYP2, leading to the reduction in length of telomeres and consequent reversal of HCC cell immortalization. Additionally, a novel targeted nanotherapy strategy was developed wherein the pcDNA-ACYP2 vector was encapsulated within polyetherimide nanoparticles (PEI/NPs), which were subsequently coated with HCC cell membranes (namely pcDNA/PEI/NPs@M). Safety and targeting characteristics abound for these nanocomposites, in both subcutaneous graft tumor models and orthotopic mouse models, they inhibited the progression of HCC by impeding TERT activity and the KCNN4/ERK pathway. In conclusion, our research identifies novel molecular mechanisms involving cytoplasmic and nuclear ACYP2 that inhibit the progression of HCC. Moreover, pcDNA/PEI/NPs@M represents a targeted therapeutic strategy for HCC that holds great promising. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s12951-024-02827-4.
An increasing body of evidence suggests that acylphosphatase-2 (ACYP2) polymorphisms are correlated with an increased susceptibility to a range of malignancies. Nevertheless, its potential functions, molecular mechanisms in hepatocellular carcinoma (HCC) and whether it can be act as a therapeutic target remain uninvestigated. Herein, ACYP2 was found to be lowly expressed in HCC and was negatively correlated with tumor size, tumor differentiation, microvascular invasion and the prognosis of HCC patients. Functional investigations revealed that overexpression of ACYP2 inhibited the proliferation and metastasis of HCC cells while promoting apoptosis; knockdown of ACYP2 had the exact opposite effect. Additionally, it was observed that ACYP2 was distributed in both the cytoplasm and nucleus of HCC cells. According to the mechanistic studies, the expression of potassium calcium-activated channel subfamily N member 4 (KCNN4) was negatively regulated by cytoplasmic ACYP2, resulting in the inhibition of K + outflow and subsequent inactivation of the ERK pathway, which impeded the growth and metastasis of HCC. Furthermore, the activity of telomerase reverse transcriptase (TERT) was inhibited by nuclear ACYP2, leading to the reduction in length of telomeres and consequent reversal of HCC cell immortalization. Additionally, a novel targeted nanotherapy strategy was developed wherein the pcDNA-ACYP2 vector was encapsulated within polyetherimide nanoparticles (PEI/NPs), which were subsequently coated with HCC cell membranes (namely pcDNA/PEI/NPs@M). Safety and targeting characteristics abound for these nanocomposites, in both subcutaneous graft tumor models and orthotopic mouse models, they inhibited the progression of HCC by impeding TERT activity and the KCNN4/ERK pathway. In conclusion, our research identifies novel molecular mechanisms involving cytoplasmic and nuclear ACYP2 that inhibit the progression of HCC. Moreover, pcDNA/PEI/NPs@M represents a targeted therapeutic strategy for HCC that holds great promising. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s12951-024-02827-4.
This review investigates the revolutionary application of cell membrane-coated nanoparticles (CMNPs) as a promising avenue for cancer therapy within the embryonic landscape of nanotechnology. Nanoparticles, pivotal in cancer treatment, are systematically examined for their diverse physicochemical structures, categorized as organic (lipid-based, protein-based, and polymer-assisted) and inorganic (carbon-based and metal) varieties. A significant focus is placed on CMNPs, which serve as an innovative drug delivery vehicle, overcoming limitations associated with conventional nanoparticle therapies. This manuscript accurately explores the advantages and challenges of various cell membranes, including those derived from cancer cells, red blood cells, platelets, stem cells, and white blood cells. Importance is placed on their roles in enhancing drug delivery precision, immune system circumvention, and targeted recognition. Detailed insights into the crafting of CMNPs are provided, elucidating membrane extraction and fusion techniques, such as sonication, extrusion, co-extrusion, and microfluidic electroporation. Maintaining membrane integrity during extraction and the benefits of coating techniques in augmenting biocompatibility and targeted drug delivery are underscored. This comprehensive resource consolidates the latest advancements in targeted drug delivery, positioning itself at the forefront of nanotechnology and biomedicine research. Encapsulating various methodologies like membrane extrusion, electrospray, and chemical conjugation, this manuscript showcases the expanding toolbox available to researchers in this dynamic field. Focusing on the unique characteristics of CMNPs, this review explores their multifaceted applications in biomedical research, particularly in tumour therapy. It provides an indepth analysis of the biocompatibility of CMNPs, their stability, immune evasion capabilities, targeted drug delivery precision, increased payload capacity, and retained biological functionality. The manuscript outlines current applications and future prospects of CMNPs in targeted chemotherapy, photothermal and photodynamic therapy, immunotherapy, gene therapy, and innovative therapeutic methods. It concludes by highlighting the advantages of CMNPs in tumour therapy and their transformative potential in reshaping the landscape of cancer treatment.
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