Extracellular vesicle-mediated delivery of circp53 suppresses the progression of multiple cancers by activating the CypD/TRAP/HSP90 pathway
Xichao Yu, Pinggang Ding, Mengjie Guo, Xiaozhu Tang, Ze Wang, Yuanjiao Zhang, Lianxin Zhou, Xinyu Lv, Hui Shi, Hongming Huang, Jialei Mao, Zhifeng Gu, Chunyan Gu, Yang Ye
Abstract
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.