Li Zhengshuo, Zhang Xiaoyue, Liu Can, Wu Yangge, Wen Yuqing, Zheng Run, Xu Chenxiao, Tian Junrui, Peng Qiu, Zheng Xiang, Wang Jia, Yan Qun, Wei Lingyu, Ma Jian
Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, Hunan, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Hunan Key Laboratory of Cancer Metabolism, Changsha, Hunan, China.
Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, Hunan, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Hunan Key Laboratory of Cancer Metabolism, Changsha, Hunan, China.
Acta Biomater. 2025 Jan 1;191:412-427. doi: 10.1016/j.actbio.2024.11.036. Epub 2024 Nov 22.
Cancer cell membrane-derived nanoparticle drug delivery system enables precise drug delivery to tumor tissues and is a new effective way to treat solid tumors. The aim of this study is to develop a safe and effective cancer cell membrane-derived nano-delivery system targeting gastric cancer. We previously reported that EPH receptor A2 (EphA2) is an important target for gastric cancer. RNA m6A methyltransferases METTL3 is upregulated in multiple cancers and promotes cancer development by increasing the expression of multiple oncogenes. We design a new nano-delivery system PLGA-STM-TAT: nanoparticles PLGA (poly lactic acid-hydroxyacetic acid) loaded with METTL3 inhibitor STM2457 and cell-penetrating peptide TAT, and then covered with gastric cancer cell membranes equipped with YSA peptides by means of click chemistry, which targeting EphA2. The nanoparticles are specifically enriched in gastric cancer tissues, significantly increased drug accumulation, and inhibited cancer cell proliferation by decreasing key oncogenes c-MYC and BRD4. During drug administration, we found that the expression of the immune checkpoint molecule PD-L1 was suppressed, and the anti-tumor immune effect was enhanced by the nano-delivery system in combination with anti-PD1. This cancer cell membrane-derived nano-delivery system provides a new biological strategy to treat gastric cancer through effective m6A modulation and EphA2 targeting. STATEMENT OF SIGNIFICANCE: M6A modifications have important biological roles, especially in tumors. Targeting highly modified m6A in gastric cancer becomes a challenge. We developed a nano-drug delivery system for modulating m6A that could produce an effective anti-cancer therapeutic effect and that the nanoparticles enhanced antitumor immunity when combined with anti-PD1.This cancer cell membrane-derived new nano-drug delivery system shows great promise as an antitumor approach by modulating m6A modification and targeting EphA2 in gastric cancers.
癌细胞膜衍生的纳米颗粒药物递送系统能够实现药物向肿瘤组织的精准递送，是治疗实体瘤的一种新型有效方法。本研究的目的是开发一种安全有效的靶向胃癌的癌细胞膜衍生纳米递送系统。我们之前报道过，EPH受体A2（EphA2）是胃癌的一个重要靶点。RNA m6A甲基转移酶METTL3在多种癌症中上调，并通过增加多种癌基因的表达促进癌症发展。我们设计了一种新的纳米递送系统PLGA-STM-TAT：负载METTL3抑制剂STM2457和细胞穿透肽TAT的纳米颗粒PLGA（聚乳酸-羟基乙酸），然后通过点击化学用配备YSA肽的胃癌细胞膜覆盖，该系统靶向EphA2。纳米颗粒在胃癌组织中特异性富集，显著增加药物积累，并通过降低关键癌基因c-MYC和BRD4抑制癌细胞增殖。在给药过程中，我们发现免疫检查点分子PD-L1的表达受到抑制，并且该纳米递送系统与抗PD1联合使用可增强抗肿瘤免疫效应。这种癌细胞膜衍生的纳米递送系统通过有效的m6A调节和EphA2靶向提供了一种治疗胃癌的新生物学策略。意义声明：M6A修饰具有重要的生物学作用，尤其是在肿瘤中。靶向胃癌中高度修饰的m6A成为一项挑战。我们开发了一种用于调节m6A的纳米药物递送系统，该系统可产生有效的抗癌治疗效果，并且纳米颗粒与抗PD1联合使用时可增强抗肿瘤免疫力。这种癌细胞膜衍生的新型纳米药物递送系统通过调节胃癌中的m6A修饰和靶向EphA2，作为一种抗肿瘤方法显示出巨大的前景。
