Simultaneously supplementing Wtp53 and degrading Mutp53 using a virus-mimicking mRNA delivery system to restore P53's autonomous anti-cancer function

The tumor suppressor protein p53 plays a critical role in preventing cancer by regulating cell cycle, apoptosis, and genomic stability. However, mutations in the P53 gene are found in over 50% of human cancers, leading to loss of its protective function or even gain of oncogenic properties. Restoring p53’s tumor-suppressing activity has long been a holy grail in cancer research, but existing strategies face challenges, particularly in tumors harboring mutant p53 (Mutp53), which can dominate over wild-type p53 (Wtp53) and drive cancer progression.

A groundbreaking study led by Professor Kaixiang Zhang from Zhengzhou University, published in Nano Research, introduces Vir-Z@R, a virus-mimicking nanosystem designed to simultaneously deliver P53 mRNA and zinc ions (Zn (II)) to tumors. This innovative approach not only replenishes Wtp53 but also selectively degrades Mutp53, effectively restoring p53’s natural anti-cancer function. The research demonstrates significant tumor growth inhibition and prolonged survival in preclinical models, offering a promising new strategy for treating p53-mutant cancers.

The team published their article in Nano Research on June 16, 2025.

“Current therapies struggle to counteract Mutp53’ s dominant-negative effects, which undermine the efficacy of p53-restoring treatments. Vir-Z@R overcomes this by degrading Mutp53 while supplementing Wtp53, a dual-action approach previously unachievable with existing technologies. The nanosystem leverages Zn (II) to destabilize Mutp53 via the ubiquitin-proteasome pathway while stabilizing Wtp53, activating apoptosis, disrupting energy metabolism, and halting tumor proliferation. Unlike small-molecule drugs targeting specific p53 mutations, Vir-Z@R’s mRNA-based strategy is adaptable to diverse p53-mutant cancers, potentially benefiting a wide patient population.”said Kaixiang Zhang.

Vir-Z@R mimics viral structures to evade immune clearance, target tumors (via RGD peptides), and escape lysosomal degradation (via L17E peptides). Its core, made of zeolitic imidazolate framework-90 (ZIF-90), releases P53 mRNA and Zn (II) in response to high ATP levels in tumor cells. In BxPC3 pancreatic cancer models (Y220C mutation), Vir-Z@R increased Wtp53 levels by 3-fold while reducing Mutp53 by 60%, triggering apoptosis and suppressing tumor growth by 93%. Transcriptomic analysis revealed Vir-Z@R disrupts glycolysis, oxidative phosphorylation, and cell-cycle pathways, amplifying oxidative stress to selectively kill cancer cells without harming normal tissues.

The research team aims to advance Vir-Z@R toward clinical trials, focusing on safety and efficacy in p53-mutant solid tumors, such as pancreatic, lung, and breast cancers. Potential integration with immunotherapy or chemotherapy could further enhance outcomes, leveraging p53 restoration to sensitize tumors to existing treatments. The virus-mimicking design could be adapted to deliver other therapeutic mRNAs or metal ions for broader oncogenic targets.

“Our work bridges a critical gap in p53-targeted therapy,”* said Professor Kaixiang Zhang, corresponding author of the study. “By combining mRNA delivery with metal ion biology, Vir-Z@R not only restores p53’s tumor-suppressing function but also eliminates the oncogenic influence of Mutp53. This approach could redefine treatment paradigms for p53-mutant cancers, which are notoriously resistant to conventional therapies.”

Other contributors include Yan Liang, Chenlu Xu, Jingge Zhang, Shuguang Li, Menghao Yin, Yinchao Li and Hua Gao from the Zhengzhou University.

This work was supported by the National Natural Science Foundations of China (Grant No. 22122409, No. 22377110, No.82402749). Henan Province Fund for Cultivating Advantageous Disciplines (No. 222301420019).

About the Authors

Zhang Kaixiang, Professor and PhD supervisor at the School of Pharmaceutical Sciences, Zhengzhou University, and recipient of the National Science Fund for Excellent Young Scholars. He obtained his Ph.D. in 2017 from the Department of Chemistry at Tsinghua University, during which he conducted joint training at the University of California, Irvine. His primary research focuses on: 1) In situ imaging analysis of gene mutations using CRISPR-based biosensors;

2) Nucleic acid nanomaterial-based drug delivery and gene therapy.

His research achievements include over 40 first-author or corresponding-author publications in prestigious journals such as Nature Communications, Journal of the American Chemical Society, Angewandte Chemie International Edition, Advanced Materials, and Chemical Society Reviews, with a total of more than 100 SCI-indexed papers and over 4,000 citations. He has led four projects funded by the National Natural Science Foundation of China as the principal investigator. For more information, please pay attention to his research homepage https://www5.zzu.edu.cn/yxy/info/1113/4101.htm

About Nano Research

Nano Research is a peer-reviewed, open access, international and interdisciplinary research journal, sponsored by Tsinghua University and the Chinese Chemical Society, published by Tsinghua University Press on the platform SciOpen. It publishes original high-quality research and significant review articles on all aspects of nanoscience and nanotechnology, ranging from basic aspects of the science of nanoscale materials to practical applications of such materials. After 18 years of development, it has become one of the most influential academic journals in the nano field. Nano Research has published more than 1,000 papers every year from 2022, with its cumulative count surpassing 7,000 articles. In 2024 InCites Journal Citation Reports, its 2024 IF is 9.0 (8.7, 5 years), and it continues to be the Q1 area among the four subject classifications. Nano Research Award, established by Nano Research together with TUP and Springer Nature in 2013, and Nano Research Young Innovators (NR45) Awards, established by Nano Research in 2018, have become international academic awards with global influence.