Researchers have achieved a significant breakthrough in cancer drug delivery by developing pH-responsive graphene oxide nanomaterials that can precisely target tumor cells while avoiding detection by the immune system. The study, led by Professor Yuta Nishina from Okayama University's Research Institute for Interdisciplinary Science in collaboration with CNRS, University of Strasbourg, was published in the journal Small on June 1, 2025.
Overcoming Immune System Detection
Cancer remains one of the leading causes of death worldwide, driving researchers to explore innovative approaches such as engineered nanomaterials (ENMs) for targeted drug delivery. While graphene oxide has gained popularity in nanotechnology due to its structural properties and ability to accumulate in tumors through the enhanced permeability and retention effect, it faces significant limitations as the immune system rapidly removes it from circulation, resulting in inefficient uptake by cancer cells.
To address this challenge, the research team designed a "charge-reversible" graphene material by attaching a hyperbranched polymer called amino-rich polyglycerol (hPGNH₂) to graphene oxide sheets and adding an adimethylmaleic anhydride (DMMA) moiety to create pH-responsive surface properties.
"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."
Optimizing Surface Chemistry for Maximum Efficacy
The team systematically analyzed three versions of the graphene oxide-polyglycerol-DMMA (GOPG-DMMA) material by varying the densities of amino groups in hPGNH₂: GOPGNH115, GOPGNH60, and GOPGNH30. The difference in amine groups altered the resultant positive charge and affected the attachment properties of the GOPG-DMMA material.
According to the results, the GOPGNH60-DMMA variant demonstrated optimal performance, achieving the right balance of safety in the bloodstream and optimal positive charge in the acidic tumor environment. This balance enabled the material to reach and enter tumor cells more efficiently while avoiding binding to healthy cells and blood proteins. The variant led to higher accumulation of nanomaterials in tumor sites with fewer side effects, confirmed through mouse model studies.
Implications for Precision Medicine
"We observed that by adjusting the surface chemistry, we could control how nanomaterials behave inside the body," says Assistant Professor Yajuan Zou. "The success of this precise control could open new avenues for 'theranostics' that integrates both cancer diagnosis and treatment."
The study represents a milestone in targeted drug delivery and provides a framework for fine-tuning pH-responsive nanomaterials for enhanced precision. The insights may also enable drug targeting within cellular compartments, particularly in acidic environments like lysosomes or endosomes, making treatments more precise while reducing harm to healthy tissue.
International Collaboration and Future Directions
The research is part of a growing international collaboration between Okayama University and CNRS, which launched the IRP C3M international research program in 2025 to develop smart nanomaterials for healthcare applications. The researchers plan to continue advancing nanomaterial technologies for improved therapeutic outcomes.
"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."
