Malignant proliferation and metastasis in non-small cell lung carcinoma (NSCLC) are great challenges for effective clinical treatment through conventional chemotherapy. The combinational therapy strategy of RNA interfering (RNAi) technology and chemotherapeutic agents have been reported to be promising for effective cancer therapy. In this study, based on multifunctional nanoparticles (NPs), the simultaneous delivery of etoposide (ETP) and anti-Enhancer of Zeste Homologue 2 (EZH2) siRNA for the effective treatment of orthotopic lung tumor was achieved. The NPs exhibited pH/redox dual sensitivity verified by particle size changes, morphological changes, and in vitro release of drugs. Confocal microscopy analysis confirmed that the NPs exhibited endosomal escape property and on-demand intracellular drug release behavior, which can protect siRNA from degradation and facilitate the chemotherapeutic effect respectively. In vitro tumor cell motility study demonstrated that EZH2 siRNA loaded in NPs can decrease the migration and invasion capabilities of tumor cells by downregulating the expression of EZH2 mRNA and protein. In particular, an antiproliferation study revealed that the co-delivery of siRNA and ETP in the multifunctional NPs can induce a synergistic therapeutic effect on NSCLC. In vivo targeting evaluation showed that cRGDyC-PEG modification on NPs exhibited a low distribution in normal organs and an obvious accumulation in orthotopic lung tumor. Furthermore, targeted NPs co-delivering siRNA and ETP showed superior inhibition on tumor growth and metastasis and produced minimal systemic toxicity. These findings indicated that multifunctional NPs can be utilized as a co-delivery system, and that the combination of EZH2 siRNA and ETP can effectively treat NSCLC.

非小细胞肺癌（NSCLC）的恶性增殖和转移是通过常规化学疗法进行有效临床治疗的巨大挑战。据报道，RNA干扰（RNAi）技术和化学治疗剂的联合治疗策略有望用于有效的癌症治疗。在这项研究中，基于多功能纳米颗粒（NPs），可以同时递送依托泊苷（ETP）和Zeste Homologue 2（EZH2）siRNA抗增强剂，以有效治疗原位肺肿瘤。NP表现出pH /氧化还原双重敏感性，已通过粒径变化，形态变化和体外验证释放药物。共聚焦显微镜分析证实，纳米粒具有内体逃逸特性和按需释放胞内药物的行为，可以保护siRNA免受降解并促进化学治疗作用。体外肿瘤细胞运动性研究表明，NPs中装载的​​EZH2 siRNA可通过下调EZH2 mRNA和蛋白的表达来降低肿瘤细胞的迁移和侵袭能力。尤其是，一项抗扩散研究表明，多功能NP中siRNA和ETP的共同传递可以诱导对NSCLC的协同治疗作用。体内靶向评估表明，对NPs的cRGDyC-PEG修饰在正常器官中分布较低，而在原位肺肿瘤中则具有明显的积累。此外，共同递送siRNA和ETP的靶向NP对肿瘤的生长和转移表现出优异的抑制作用，并产生最小的全身毒性。这些发现表明多功能NP可以用作共递送系统，并且EZH2 siRNA和ETP的组合可以有效治疗NSCLC。