A team of researchers at the National University of Singapore (NUS) has developed a groundbreaking gene delivery platform that could revolutionize cancer immunotherapy manufacturing and accessibility. The technology, called Nanostraw Electro-actuated Transfection (NExT), efficiently delivers genetic material into human immune cells using tiny hollow nanostructures and mild electrical pulses.
Led by Assistant Professor Andy Tay from the Department of Biomedical Engineering and the Institute for Health Innovation and Technology at NUS, the research team demonstrated that NExT can transfect over 14 million immune cells in a single run. The findings were published in the journal Biomaterials on January 5, 2025.
Overcoming Limitations in Current Gene Delivery Methods
Cancer immunotherapies, particularly chimeric antigen receptor T-cell (CAR-T) therapies, have shown remarkable success in treating blood cancers. However, these treatments remain prohibitively expensive and logistically complex. In Singapore, a single CAR-T cell infusion costs approximately S$670,000, with subsidies covering only a fraction of this amount.
"Although subsidies are available, they typically cover only a fraction of the cost. This may limit access to the therapy for a significant number of patients, even as demand grows," explained Assistant Professor Tay.
One of the major bottlenecks in CAR-T manufacturing is the delivery of genetic material into immune cells. Current industry-standard methods include viral vectors and bulk electroporation, both with significant drawbacks. Viral approaches raise concerns about safety, immunogenicity, and random gene integration, while bulk electroporation can damage cells and reduce their therapeutic quality.
How the NExT Platform Works
The NExT platform overcomes these limitations through an innovative approach. It interfaces cells with a dense forest of nanostraws — microscopic hollow tubes less than a thousandth the width of a human hair. When a mild electrical signal is applied, these nanostraws create temporary pores in the cell membrane, allowing biomolecules such as mRNA or CRISPR/Cas9 complexes to enter the cell cytoplasm directly.
"Think of gene delivery like selecting a food delivery service. Ideally you want one that's fast, reliable, keeps the food fresh and doesn't cost a fortune. That's what gene delivery should be like — efficient, cost-effective, doesn't stress the cells too much, and adaptable to many different 'orders', or biomolecules," said Arun Kumar, the paper's first author and a PhD student supervised by Assistant Professor Tay.
The platform has demonstrated remarkable versatility, successfully transfecting difficult-to-engineer immune cell types including gamma-delta T cells, T regulatory cells, dendritic cells, macrophages, natural killer cells, and neutrophils — all of which are being explored as alternative immune cell therapies.
Impressive Preclinical Results
In preclinical experiments, the NExT platform achieved transfection efficiencies of up to 94% for proteins and over 80% for mRNA in primary T cells. Crucially, the cells maintained their key biological functions such as proliferation, migration, and cytokine production after transfection.
"We were very encouraged to see that even after transfection, the immune cells retained their essential tumour-fighting characteristics. This suggests that the platform delivers both the efficiency as well as the cell quality needed for effective therapy," noted Assistant Professor Tay.
Potential Impact on Cancer Treatment Accessibility
The high-throughput nature of the NExT platform addresses the scale and cost bottlenecks of cell therapy production. Its multi-well version can transfect over 14 million cells in a single run, enabling the simultaneous delivery of different genetic cargoes into multiple immune cell types from various donors, thereby reducing production time.
Furthermore, the platform can engineer alternative immune cells that are less likely to trigger severe immune reactions and, in some cases, can function without matching the patient's immune profile. This makes them suitable for "off-the-shelf" allogeneic therapies, which could further improve accessibility.
Path to Clinical Translation
The NUS research team is now working to validate the technology in further preclinical studies before advancing to human trials. They are also collaborating with industry partners to explore how the system can be integrated into existing cell therapy manufacturing workflows.
This development comes at a significant time for Singapore's healthcare system. On August 1, 2024, the Singapore Ministry of Health began providing subsidies for cell, tissue, and gene therapy products (CTGTPs) that are assessed to be clinically and cost-effective. The first CTGTP eligible for subsidy is tisagenlecleucel, a type of CAR-T cell therapy for treating blood cancers.
If successfully translated to clinical practice, the NExT platform could substantially reduce the manufacturing costs of these advanced therapies, potentially making life-saving treatments accessible to a broader patient population both in Singapore and globally.
