Engineered hUCMSC-derived extracellular vesicles deliver circ-0000258 to restore p53-mediated tumor suppression in
Chan Zhang1, Lei Li2, Yanxiu Liu3
1Institute of Medical Research, Northwestern Polytechnical University, Xi'an, Shaanxi, China.
Introduction:
Papillary thyroid carcinoma (PTC) is a significant type of endocrine cancer, characterized by diverse genetic alterations and a complex molecular environment. Extracellular vesicles (EVs), especially those derived from mesenchymal stem cells (MSCs), have emerged as promising targeted drug carriers for cancer cells. Additionally, reprogramming MSC-derived EVs represents a novel strategy for cancer gene therapy, offering potential solutions to clinical challenges and new treatment directions. Increasing evidence suggests that MSC-derived EVs play a crucial role in tumor progression by delivering circular RNAs (circRNAs), which function as microRNA (miRNA) sponges. However, the underlying molecular mechanisms and their clinical applications remain to be fully explored and validated.
Methods And Results:
Through in-depth mining using high-throughput bioinformatics analyses, we conducted a comprehensive differential gene analysis between PTC tissues and normal thyroid tissues, successfully identifying circ-0000258 as a key regulatory molecule. Following multi-dimensional validation in PTC cell lines and clinical specimens, the consistent low expression of circ-0000258 was confirmed, strongly suggesting its latent potential as a tumor suppressor. Functional mechanistic investigations have revealed that overexpression of circ-0000258 potently curbs the malignant biological behaviors of PTC cells, notably inhibiting cell proliferation and invasion. More significantly, circ-0000258 acts as a molecular sponge, specifically sequestering miR-146b. This action relieves the post-transcriptional repression of p53 by miR-146b, thereby activating the p53-mediated apoptotic signaling cascade. By intervening at the genetic regulatory level, circ-0000258 effectively reprograms the fate of thyroid tumor cells. Furthermore, in the context of translational medicine research, we innovatively constructed an engineered delivery platform based on extracellular vesicles derived from human umbilical cord mesenchymal stem cells (hUCMSC-EVs). By exogenously loading circ-0000258 into these vesicles, we successfully endowed these natural nanocarriers with targeted anti-cancer properties. Both in vitro and in vivo functional assays demonstrated that the engineered hUCMSC-EVs loaded with circ-0000258 could effectively act on PTC cells, significantly reducing the volume of xenograft tumors and inducing tumor cell apoptosis. Notably, when combined with cisplatin, these engineered extracellular vesicles exhibited a synergistic anti-cancer effect, suggesting their potential to overcome chemoresistance in thyroid tumors.
Conclusion:
This study has established the circ-0000258/miR-146b/p53 regulatory axis as a crucial mechanism underlying tumor suppression in PTC. It has also demonstrated the translational potential of hUCMSC-EVs as a safe and efficient delivery vehicle. By integrating the functional role of circ-0000258 with the targeted delivery advantages of engineered EVs, this research not only provides a novel strategy for the targeted treatment of thyroid cancer but also offers a theoretical basis and technical paradigm for the development of novel anti-tumor biological agents. It is anticipated to advance the field of precision oncology to a new level.
