Ultrasound-mediated PLGA-PEI Nanobubbles Carrying STAT6 SiRNA Enhances NSCLC Treatment via Repolarizing Tumor-associated Macrophages from M2 to M1 Phenotypes.

IF 2.8 4区医学 Q2 PHARMACOLOGY & PHARMACY Current drug delivery Pub Date : 2024-01-01 DOI:10.2174/1567201820666230724151545

Hong Shu, Wenhao Lv, Zhi-Jian Ren, Hui Li, Tiantian Dong, Yao Zhang, Fang Nie

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Abstract

Background: Tumor-associated macrophages (TAMs) are crucial for non-small cell lung cancer (NSCLC) development.

Objective: In this study, polylactic acid-co-glycolic acid (PLGA)-polyethylenimine (PEI) nanobubbles (NBs) carrying STAT6 siRNA were prepared and combined with ultrasound-mediated nanobubbles destruction (UMND) to silence the STAT6 gene, ultimately repolarizing TAMs from the M2 to the M1 phenotype, treating NSCLC in vitro.

Methods: PLGA-PEI NBs-siRNA were prepared and characterised, and their respective ultrasound imaging, biological stabilities and cytotoxicities were detected. Transfection efficiency was evaluated by fluorescence microscopy and flow cytometry. Repolarization of THP-1-derived M2-like macrophages was determined by qPCR and flow cytometry. NSCLC cells (A549) were co-cultured with transfected M2-like macrophages or their associated conditioned medium (CM). Western blotting was used to detect STAT6 gene silencing in M2-like macrophages and markers of epithelial and mesenchymal in A549 cells. The proliferation of A549 cells was detected using CCK-8 and cell colony formation assays. Transwell assays were used to detect the migration and invasion of A549 cells.

Results: PLGA-PEI NBs-siRNA had an average size of 223.13 ± 0.92 nm and a zeta potential of about -5.59 ± 0.97 mV. PLGA-PEI NBs showed excellent ultrasonic imaging capability in addition to biological stability to protect siRNA from degradation. UMND enhanced PLGA-PEI NBs-STAT6 siRNA transfection in M2-like macrophages, which made M2-like macrophages repolarize to M1-like macrophages and prevented proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) in A549 cells.

Conclusion: UMND enhanced PLGA-PEI NBs-STAT6 siRNA to repolarize TAMs from the M2 to the M1 phenotype, thus treating NSCLC. These findings provide a promising therapeutic approach for enhancing NSCLC immunotherapy.

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超声波介导的携带 STAT6 SiRNA 的 PLGA-PEI 纳米气泡能使肿瘤相关巨噬细胞从 M2 型恢复到 M1 型，从而增强对 NSCLC 的治疗。

背景：肿瘤相关巨噬细胞（TAM肿瘤相关巨噬细胞（TAMs）对非小细胞肺癌（NSCLC）的发展至关重要：本研究制备了携带STAT6 siRNA的聚乳酸-共聚乙醇酸（PLGA）-聚乙烯亚胺（PEI）纳米气泡（NBs），并结合超声介导的纳米气泡破坏（UMND）来沉默STAT6基因，最终将TAMs从M2表型重新极化为M1表型，在体外治疗NSCLC：方法：制备并表征了 PLGA-PEI NBs-siRNA，并检测了它们各自的超声成像、生物稳定性和细胞毒性。荧光显微镜和流式细胞术评估了转染效率。THP-1 衍生的 M2 样巨噬细胞的再极化是通过 qPCR 和流式细胞仪测定的。NSCLC细胞（A549）与转染的M2样巨噬细胞或其相关的条件培养基（CM）共培养。用 Western 印迹法检测 M2 样巨噬细胞中的 STAT6 基因沉默以及 A549 细胞中上皮和间质的标记。使用 CCK-8 和细胞集落形成试验检测 A549 细胞的增殖情况。Transwell试验用于检测A549细胞的迁移和侵袭：结果：PLGA-PEI NBs-siRNA 的平均尺寸为 223.13 ± 0.92 nm，zeta 电位约为 -5.59 ± 0.97 mV。PLGA-PEI NBs 除了具有保护 siRNA 不被降解的生物稳定性外，还具有出色的超声波成像能力。UMND增强了PLGA-PEI NBs-STAT6 siRNA在M2样巨噬细胞中的转染，使M2样巨噬细胞重新极化为M1样巨噬细胞，阻止了A549细胞的增殖、迁移、侵袭和上皮-间质转化（EMT）：UMND增强了PLGA-PEI NBs-STAT6 siRNA使TAMs从M2表型重新极化为M1表型的能力，从而治疗了NSCLC。这些发现为增强 NSCLC 免疫疗法提供了一种前景广阔的治疗方法。

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来源期刊

Current drug delivery PHARMACOLOGY & PHARMACY-

CiteScore

5.10

自引率

4.20%

发文量

170

期刊介绍： Current Drug Delivery aims to publish peer-reviewed articles, research articles, short and in-depth reviews, and drug clinical trials studies in the rapidly developing field of drug delivery. Modern drug research aims to build delivery properties of a drug at the design phase, however in many cases this idea cannot be met and the development of delivery systems becomes as important as the development of the drugs themselves. The journal aims to cover the latest outstanding developments in drug and vaccine delivery employing physical, physico-chemical and chemical methods. The drugs include a wide range of bioactive compounds from simple pharmaceuticals to peptides, proteins, nucleotides, nucleosides and sugars. The journal will also report progress in the fields of transport routes and mechanisms including efflux proteins and multi-drug resistance. The journal is essential for all pharmaceutical scientists involved in drug design, development and delivery.