除了抑制持续炎症外，磷酸酶与120具体霍姆兹于染色体10上的基因删失（PTEN）也被认为是缓解类风湿性关节炎（RA）症状的重要治疗靶点。使用信使RNA（mRNA）在滑膜组织中调节PTEN基因表达是一种有前途的对抗RA的方法。然而，mRNA治疗往往受到不令人满意的稳定性和在滑膜组织中的低效定位的阻碍。本研究提出了一种基因工程仿生膜包被的mRNA（MR@P-mPTEN）载体，能够将mRNA-PTEN（mPTEN）直接输送到RA关节中。通过质粒转染，在巨噬细胞仿生膜上过表达肿瘤坏死因子（TNF-α）受体，制备了减少炎症通路激活的诱饵用于TNF-α。得到的构建物MR@P-mPTEN通过体内荧光成像显示出良好的稳定性和RA靶向。同时发现MR@P-mPTEN在体外和体内通过与TNF-α竞争结合并激活PTEN通路，从而抑制滑膜炎和关节损伤。临床微型计算机断层扫描和组织学分析证实了治疗效果。这些结果表明，基因工程仿生治疗平台MR@P-mPTEN既能抑制促炎细胞因子，又能上调PTEN蛋白表达以缓解RA损伤，为RA治疗提供了一种新的组合策略。（© 2023 Wiley-VCH GmbH)

In addition to inhibiting persistent inflammation, phosphatase and tensin homolog deleted from chromosome 10 (PTEN) is known as an important therapeutic target for alleviating rheumatoid arthritis (RA) symptoms. Modulation of PTEN gene expression in synovial tissue using messenger RNA (mRNA) is a promising approach to combat RA. However, mRNA therapeutics are often hampered by unsatisfactory stability and inefficient localization in synovial tissue. In this study, a genetically engineered biomimetic membrane-coated mRNA (MR@P-mPTEN) carrier that effectively delivers mRNA-PTEN (mPTEN) directly to the RA joint is presented. By overexpressing tumor necrosis factor (TNF-α) receptors on macrophage biomimetic membranes via plasmid transfection, decoys that reduce inflammatory pathway activation are prepared for TNF-α. The resulting construct, MR@P-mPTEN, shows good stability and RA targeting based on in vivo fluorescence imaging. It is also found that MR@P-mPTEN competitively binds TNF-α and activates the PTEN pathway in vitro and in vivo, thereby inhibiting synovitis and joint damage. Clinical micro-computed tomography and histological analyses confirm the treatment effects. These results suggest that the genetically engineered biomimetic therapeutic platform MR@P-mPTEN both inhibits pro-inflammatory cytokines and upregulates PTEN protein expression to alleviate RA damage, providing a new a new combination strategy for RA treatment.© 2023 Wiley-VCH GmbH.