Cancer remains one of the leading causes of death worldwide, and despite advancements in diagnosis and treatment, it continues to impose a significant health burden globally. Researchers have now started exploring various innovative methods, such as engineered nanomaterials (ENMs) that can enable targeted drug delivery to cancer cells. While promising, the in vivo behavior of pH-responsive ENMs, which continuously interact with body fluids once administered, remains poorly understood.
To address this research gap, a team of researchers led by Professor Yuta Nishina from the Research Institute for Interdisciplinary Science, Okayama University, Japan, in collaboration with Assistant Professor Yajuan Zou from the same institution and Professor Alberto Bianco from CNRS, University of Strasbourg, France, aimed to investigate how pH-responsive ENMs convert their properties into dynamic interactions with proteins and cells in vivo. Their findings were published online in the journal Small on June 01, 2025.
Graphene oxide—a carbon-based nanomaterial obtained from graphite—has recently gained popularity in nanotechnology due to its structural properties and its ability to accumulate in tumors through the enhanced permeability and retention effect. However, it faces limited applications because the immune system rapidly removes it from the circulation, resulting in inefficient uptake by cancer cells.
To overcome this barrier, the researchers designed a "charge-reversible" graphene material by attaching a hyperbranched polymer called amino-rich polyglycerol (hPGNH₂) to graphene oxide sheets and then adding an adimethylmaleic anhydride (DMMA) moiety to make the surface pH-responsive.
"When the material is in the neutral pH of the bloodstream, its surface remains negatively charged, avoiding detection by the immune system," explains Prof. Nishina. "But when it enters the slightly acidic environment of a tumor, its surface becomes positively charged, helping it bind to and enter cancer cells."
The team analyzed three versions of this graphene oxide-polyglycerol-DMMA (GOPG-DMMA) material by varying the densities of amino groups in hPGNH₂. These groups included GOPGNH115, GOPGNH60, and GOPGNH30. The difference in amine groups altered the resultant positive charge and thereby affected the attachment of the GOPG-DMMA material.
According to the results, the GOPGNH60-DMMA variant worked best, achieving the right balance of safety in the bloodstream and optimal positive charge in the acidic tumor environment. This balance allowed the material to reach and enter the tumor cells more efficiently while avoiding binding to healthy cells and blood proteins. Moreover, it led to higher accumulation of nanomaterials in tumor sites with fewer side effects, which was confirmed through mouse models.
"We observed that by adjusting the surface chemistry, we could control how nanomaterials behave inside the body," says Dr. Zou. "The success of this precise control could open new avenues for 'theranostics' that integrates both cancer diagnosis and treatment."
The study marks a milestone in targeted drug delivery and can help fine-tune such pH-responsive nanomaterials for more precision. Insights from the study may also help target drugs inside cells—especially in acidic compartments like lysosomes or endosomes—making treatments more precise and reducing harm to healthy tissue.
The study is part of a growing international collaboration. In 2025, Okayama University and CNRS launched the IRP C3M international research program, which aims to create more smart nanomaterials for healthcare. In the future, the researchers will continue pushing the limits of nanomaterials for better therapies.
"We now have a concrete guideline for improving the performance of pH-responsive nanomedicines," said Prof. Nishina. "With this discovery, we are one step closer to the future of personalized medicine."
About Okayama University, Japan
As one of the leading universities in Japan, Okayama University aims to create and establish a new paradigm for the sustainable development of the world. Okayama University offers a wide range of academic fields, which become the basis of the integrated graduate schools. This not only allows us to conduct the most advanced and up-to-date research, but also provides an enriching educational experience.
Website: https://www.okayama-u.ac.jp/index_e.html
About Professor Yuta Nishina from Okayama University, Japan
Dr. Yuta Nishina is a Professor and a leading researcher at the Research Institute for Interdisciplinary Science at Okayama University, Japan. He holds a PhD in Engineering from the Graduate School of Okayama University, Japan, and has expertise in multidisciplinary research, including nanocarbons, biomedicals, catalysis, and energy-related devices based on organic chemistry. He has over 210 peer-reviewed articles, 25 patents, and 14 book chapters to his credit. Currently, he is a part of the ongoing collaboration with the University of Strasbourg and CNRS to develop tunable, pH-responsive graphene-based nanocarriers for theranostics and precision drug delivery.
