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<p>The majority of cancers remain incurable due to limited therapeutic responses in malignancies with high-risk genetic mutations such as <i>TP53</i>. Building on the success of mRNA vaccine technology, we investigated circular RNA (circRNA) therapeutics and identified hsa_circp53_0041947, a <i>TP53</i>-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 <i>TP53</i> pathway alterations.</p>

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Extracellular vesicle-mediated delivery of circp53 suppresses the progression of multiple cancers by activating the CypD/TRAP/HSP90 pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月1日

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  • Xichao Yu,
  • Pinggang Ding,
  • Mengjie Guo,
  • Xiaozhu Tang,
  • Ze Wang,
  • Yuanjiao Zhang,
  • Lianxin Zhou,
  • Xinyu Lv,
  • Hui Shi,
  • Hongming Huang,
  • Jialei Mao,
  • Zhancheng Gu,
  • Chunyan Gu,
  • Ye Yang

摘要

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.