Non-small cell lung cancer (NSCLC) is the leading cause of lung cancer-related deaths worldwide. Tumor-associated macrophages (TAMs), which can be polarized into tumor-promoting M2 phenotype, overexpress folate receptor beta (FRβ) and are associated with poor prognosis in NSCLC. In addition, calpain-2 (CAPN2) is overexpressed in NSCLC and is involved in tumor growth. To improve the anticancer efficacy of drugs and reduce their side effects in the treatment of NSCLC, it is important to develop smart drug delivery systems with specific targeting ability and controlled release mechanisms. In this study, FRβ-targeted pH-sensitive liposomes were designed as carriers to ensure efficient drug delivery and acid-responsive release in NSCLC cells. Folate-mediated targeting of FRβ in M2 TAMs and NSCLC cells effectively inhibited tumor growth and the stimulus-responsive drug release reduced the toxic side effects of the drug. The combination of doxycycline (anti-CAPN2) and docetaxel (anticancer drug) showed a synergistic inhibitory effect on tumor growth by suppressing CAPN2 expression.

非小细胞肺癌（NSCLC）是全球肺癌相关死亡的主要原因。肿瘤相关的巨噬细胞（TAM），可以极化成促进肿瘤的M2表型，过表达叶酸受体β（FRβ），并且与NSCLC的不良预后有关。此外，钙蛋白酶2（CAPN2）在NSCLC中过表达，并参与肿瘤的生长。为了提高药物的抗癌功效并减少其在NSCLC治疗中的副作用，重要的是开发具有特定靶向能力和控释机制的智能药物递送系统。在这项研究中，针对FRβ的pH敏感脂质体被设计为载体，以确保在NSCLC细胞中有效的药物递送和酸响应释放。叶酸介导的对M2 TAM和NSCLC细胞中FRβ的靶向有效抑制了肿瘤的生长，刺激反应性药物的释放降低了该药物的毒副作用。强力霉素（抗CAPN2）和多西他赛（抗癌药）的组合通过抑制CAPN2的表达，对肿瘤的生长具有协同抑制作用。