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

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.