Bioinspired prodrug nanoassemblies with dual PEGylation and membrane-coating strategies to enhance membrane binding stability and antitumor efficacy
New strategy combines PEG and cell membrane modifications to overcome limitations of traditional biomimetic nano formulations
image: The CM-pDPNA system uses γ-4S-2CTX to self-assemble into uniform nanoparticles, which are then modified with PEG and tumor cell membranes. This dual camouflage improves nanoparticle stability, tumor specificity, and immune evasion.
Credit: Nano Research, Tsinghua University Press
Researchers from Shenyang Pharmaceutical University and Kyoto University have designed a novel tumor-targeting nanomedicine that combines two key elements: a self-assembly prodrug nanostructure and dual-surface modification using both DSPE-PEG2k and tumor cell membranes. The strategy offers an effective solution to limitations of current drug delivery systems, such as low drug loading, premature leakage, and poor in vivo stability.
The study, led by Prof. Jin Sun and Prof. Bingjun Sun, in collaboration with Associate Prof. Yuki Takahashi, introduces a cell membrane-camouflaged prodrug nanomedicine (CM-pDPNAs), where the core is composed of a carrier-free self-assembly prodrug, γ-4S-2CTX—a dimeric cabazitaxel molecule bridged via redox-sensitive tetrasulfide bonds.
“Our goal was to fundamentally overcome the dependency on traditional nanocarriers,” said the research team. “By letting the prodrug molecule itself form stable nanoparticles, we eliminate the need for additional carrier materials, which often limit drug loading and contribute to potential toxicity.”
The γ-4S-2CTX nanostructures demonstrated uniform particle size, high colloidal stability, and controlled drug release in response to glutathione (GSH), a hallmark of the tumor microenvironment. To enhance tumor targeting and prolong circulation time, the researchers coated the prodrug nanoparticles with tumor-derived cell membranes and stabilized the interface using DSPE-PEG2k.
In vitro and in vivo studies revealed that CM-pDPNAs exhibit superior tumor cell uptake, immune evasion through CD47-mediated phagocytosis suppression, and enhanced antitumor activity with minimal systemic toxicity. Pharmacokinetic analysis showed prolonged blood circulation and increased tumor accumulation compared to both unmodified and single-modified nanoparticle formulations.
The findings, published in Nano Research, highlight the potential of rationally engineered prodrug nanomedicines to achieve high efficacy with simplified formulation steps.
“This dual-modification strategy integrates the structural simplicity of prodrug self-assembly with the functional benefits of biomimicry,” said the research team. “It offers a path toward smarter, safer, and more effective cancer therapies.”
The authors expect that this approach can be extended to other types of chemotherapy agents and could accelerate the clinical translation of carrier-free nanomedicine platforms.
Other contributors include Qing Wang, Xiaoning Su, Jiayu Guo, Lingxiao Li, Tian Liu, Zhonggui He from Wuya College of Innovation at Shenyang Pharmaceutical University in Shenyang, China, and Xin Li from Department of Respiratory Disease, The First Affiliated Hospital at Jinzhou Medical University, in Jinzhou, China.
This work was supported by the National Key R&D Program of China (No. 2022YFE0111600), National Natural Science Foundation of China (No. 82204318), Key research and development program of Liaoning Province (2024JH2/102500061), Youth innovation team of Liaoning Province Department of Education (No. LJ222410163049), Liaoning Revitalization Talents Program (No. XLYC2203083).
About the Authors
Shiyi Zuo is a Ph.D. student at the School of Wuya Innovation and the School of Pharmacy, Shenyang Pharmaceutical University. She is the first author of the study and focuses her research on self-assembly prodrugs and biomimetic drug delivery systems.
Prof. Jin Sun is the academic Dean of the School of Wuya Innovation and the School of Pharmacy at Shenyang Pharmaceutical University. He serves as the principal investigator of the research group and corresponding author of the paper. Prof. Sun’s research centers on prodrugs, nanomedicine, and biomimetic drug delivery systems. He has published over 230 SCI papers in high-impact journals including Nature Communications and Science Advances, with an H-index of 39 and more than 4,500 citations. He is a recipient of China’s “Ten Thousand Talents Program” and a Distinguished Professor of the “Changjiang Scholars Program” by the Ministry of Education.
Prof. Bingjun Sun is a professor and principal investigator at the School of Wuya Innovation, Shenyang Pharmaceutical University. His research focuses on self-assembly prodrug-based nanodelivery systems. He has published over 60 SCI papers as first or corresponding author in prestigious journals such as Nature Communications and Science Advances. Prof. Sun is a recipient of several awards, including the Young Talent of the “Xingliao Talents Program,” the National Postdoctoral Innovative Talent Support Program, and the First Prize of the Natural Science Award of Liaoning Province. He also serves as a youth editorial board member for Asian Journal of Pharmaceutical Sciences, View, and Acta Materia Medica.
Dr. Yuki Takahashi is an Associate Professor at the Graduate School of Pharmaceutical Sciences, Kyoto University. His research interests include biopharmaceutics, drug delivery systems, gene therapy, and extracellular vesicles (especially exosomes). He is particularly focused on developing long-circulating and tumor-targeting nanomedicines with immunomodulatory functions. Dr. Takahashi previously worked as a postdoctoral researcher at the University of Pittsburgh and has published extensively in the fields of nanomedicine and exosome therapeutics. He is a recipient of the Young Investigator Awards from both the Academy of Pharmaceutical Science and the Pharmaceutical Society of Japan.
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.