The reversion of DNA methylation-induced miRNA silence via biomimetic nanoparticles-mediated gene delivery for efficient lung adenocarcinoma therapy

Abstract

Background Lung cancer is one of the fatal cancers worldwide, and over 60% of patients are lung adenocarcinoma (LUAD). Our clinical data demonstrated that DNA methylation of the promoter region of miR-126-3p was upregulated, which led to the decreased expression of miR-126-3p in 67 cases of lung cancer tissues, implying that miR-126-3p acted as a tumor suppressor. Transduction of miR-126-3p is a potential therapeutic strategy for treating LUAD, yet the physiological environment and properties of miRNA challenge current transduction approaches. Methods We evaluated the expression of miR-126-3p in 67 pairs of lung cancer tissues and the corresponding adjacent non-tumorous tissues by Reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The relationship between the overall survival of lung cancer patients and miR-126-3p was analyzed by the Cancer Genome Atlas cohort database (Oncolnc, http://www.oncolnc.org). We analyzed DNA methylation Methylation-specific PCR (MSP) analysis. To determine whether ADAM9 is the direct target of miR-126-3p, we performed the 3′-UTR luciferase reporter assay. The protein levels in the cells or tissues were evaluated with western blotting (WB) analysis. The biodistribution of nanoparticles were monitored by in vivo tracking system. Results We describe the development of novel stealth and matrix metalloproteinase 2 (MMP2)-activated biomimetic nanoparticles, which are constructed using MMP2-responsive peptides to bind the miR-126-3p (known as MAIN), and further camouflaged with red blood cell (RBC) membranes (hence named REMAIN). REMAIN was able to effectively transduce miRNA into lung cancer cells and release them via MMP2 responsiveness. Additionally, REMAIN possessed the advantages of the natural RBC membrane, including extended circulation time, lower toxicity, better biocompatibility, and immune escape. Moreover, in vitro and in vivo results demonstrated that REMAIN effectively induced apoptosis of lung cancer cells and inhibited LUAD development and progression by targeting ADAM9. Conclusion The novel style of stealth and MMP2-activated biomimetic nanoparticles show great potential in miRNA delivery.

Expression patterns of platinum resistance-related genes in lung adenocarcinoma and related clinical value models

“…However, the intracellular oxidation–reduction system of many tumor cells is out of balance, and so the drug resistance of LUAD cells is also closely related to oxidative stress ( Winterbourn, 2008 ). There is DNA recombination in the GO pathway of gene enrichment, and the study shows that the occurrence and development of lung adenocarcinoma are closely related to it ( Liang et al, 2022 ). We speculate that platinum resistance of lung adenocarcinoma is also closely related to it, and we will focus on it in the follow-up research.…”

IBPGNET: lung adenocarcinoma recurrence prediction based on neural network interpretability

“…Protein concentrations were quantified using the BCA Protein Assay Kit (Solarbio, China). The WB was performed as previously reported [ 26 ].…”

Biomimetic Nano-Drug Delivery System: An Emerging Platform for Promoting Tumor Treatment

“…The results indicate this biomimetic hybrid nanoenzyme can enhance the starvation therapy and photodynamic therapy of hypoxic tumors by self-supplying H + and accelerating O 2 generation. 83 Liang et al 84 used RBCM to encapsulate NPs in which matrix metalloproteinase 2-cleavable peptides and miR-126-3p self-assemble. The obtained stealth BNDDS was used for efficient lung adenocarcinoma therapy by reversing DNA methylation-induced miRNA silencing ( Figure 3A ).…”