Yu Xichao, Ding Pinggang, Guo Mengjie, Tang Xiaozhu, Wang Ze, Zhang Yuanjiao, Zhou Lianxin, Lv Xinyu, Shi Hui, Huang Hongming, Mao Jialei, Gu Zhancheng, Gu Chunyan, Yang Ye
Kunshan Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Kunshan, China.
School of Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
Exp Mol Med. 2025 Aug 1. doi: 10.1038/s12276-025-01506-0.
The majority of cancers remain incurable due to limited therapeutic responses in malignancies with high-risk genetic mutations such as TP53. Building on the success of mRNA vaccine technology, we investigated circular RNA (circRNA) therapeutics and identified hsa_circp53_0041947, a TP53-derived circRNA in multiple myeloma (MM). The hsa_circp53_0041947 encodes a functional peptide (circp53-209aa) demonstrating p53 mutation-independent anti-MM effects through CypD/TRAP1/HSP90 complex-mediated mechanisms. Specifically, circp53-209aa activated cyclophilin D (CypD) isomerase activity at the circp53-209aa-R175 site, triggering mitochondrial permeability transition pore opening and subsequent mitochondrial apoptosis. To enable targeted delivery, we engineered extracellular vesicle (EV) systems, E7-Lamp2b-EVs and Her2-Lamp2b-EVs, for MM and colorectal cancer, respectively. Circp53-EVs administration achieved tumor-selective growth inhibition in both malignancies. Our study establishes engineered circp53-EVs as a versatile therapeutic platform, demonstrating the translational potential of circRNA-based strategies for refractory cancers with TP53 pathway alterations.
由于在具有高风险基因突变（如TP53）的恶性肿瘤中治疗反应有限，大多数癌症仍然无法治愈。基于mRNA疫苗技术的成功，我们研究了环状RNA（circRNA）疗法，并在多发性骨髓瘤（MM）中鉴定出hsa_circp53_0041947，一种源自TP53的circRNA。hsa_circp53_0041947编码一种功能性肽（circp53-209aa），通过CypD/TRAP1/HSP90复合物介导的机制表现出与p53突变无关的抗MM作用。具体而言，circp53-209aa在circp53-209aa-R175位点激活亲环蛋白D（CypD）异构酶活性，触发线粒体通透性转换孔开放并随后导致线粒体凋亡。为了实现靶向递送，我们分别为MM和结直肠癌设计了细胞外囊泡（EV）系统，即E7-Lamp2b-EV和Her2-Lamp2b-EV。Circp53-EV给药在这两种恶性肿瘤中均实现了肿瘤选择性生长抑制。我们的研究将工程化的circp53-EV确立为一种通用的治疗平台，证明了基于circRNA的策略对于具有TP53通路改变的难治性癌症的转化潜力。
