非小细胞肺癌 (NSCLC) 中 microRNA-155 (miR-155) 表达升高会促进顺铂耐药并对治疗结果产生负面影响。然而，miR-155 还可以通过抑制 PD-L1 表达来增强抗肿瘤免疫。由于其双分子效应，通过其拮抗剂抗 miR-155 来靶向治疗 miR-155 已被证明具有挑战性。我们开发了一种多尺度机制模型，用体内数据进行校准，然后外推到人类，以研究 miR-155 的治疗效果纳米颗粒在 NSCLC 中单独或与标准治疗药物联合使用抗 miR-155。模型模拟和临床情况分析表明，抗 miR-155 单一疗法以 2.5 mg/kg 的剂量给药一次每三周一次就有显着的抗癌活性。它的中位无进展生存期 (PFS) 为 6.7 个月，优于顺铂和免疫检查点抑制剂。此外，我们探索了抗 miR-155 与标准治疗药物的组合，发现了两种和三种药物组合具有很强的协同作用。抗 miR-155、顺铂和派姆单抗三药组合的中位 PFS 为 13.1 个月，而抗 miR-155 和顺铂的两种药物组合的中位 PFS 为 11.3 个月。由于其简单的设计和成本效益，成为更实用的选择。我们的分析还为药物组合的不利剂量比提供了宝贵的见解，强调了优化剂量方案以防止拮抗作用的必要性。这项工作弥合了抗 miR-155 的临床前开发和临床转化之间的差距，并揭示了抗 miR-155 的潜力。 NSCLC 中的 miR-155 联合疗法。© 2024。作者。

Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects.We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs.Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg administered once every three weeks has substantial anti-cancer activity. It led to a median progression-free survival (PFS) of 6.7 months, which compared favorably to cisplatin and immune checkpoint inhibitors. Further, we explored the combinations of anti-miR-155 with standard-of-care drugs, and found strongly synergistic two- and three-drug combinations. A three-drug combination of anti-miR-155, cisplatin, and pembrolizumab resulted in a median PFS of 13.1 months, while a two-drug combination of anti-miR-155 and cisplatin resulted in a median PFS of 11.3 months, which emerged as a more practical option due to its simple design and cost-effectiveness. Our analyses also provided valuable insights into unfavorable dose ratios for drug combinations, highlighting the need for optimizing dose regimens to prevent antagonistic effects.This work bridges the gap between preclinical development and clinical translation of anti-miR-155 and unravels the potential of anti-miR-155 combination therapies in NSCLC.© 2024. The Author(s).