Nonviral Gene Delivery Platform Offers Promise for Cancer Treatment and Cell Therapy

University of Michigan researchers developed serum albumin-based nanoparticles that delivered plasmid DNA and mRNA into multiple human cell types without viral vectors. Published in Advanced Materials, the platform achieved over 95% uptake, remained stable for 12 days, and efficiently transfected primary human T cells with high viability. The approach could support safer gene therapies for cancer and many other genetic diseases by reducing risks associated with viral delivery.

Gene therapy has transformed the treatment of several blood disorders and cancers, but its delivery systems still carry serious liabilities. Many approved approaches rely on modified viruses to shuttle therapeutic genes into cells. That strategy can work remarkably well, yet it also comes with biological risk: immune overreactions, inflammatory toxicity, and insertion of viral cargo into the genome in ways that disrupt tumor-suppressor genes and may contribute to secondary cancers.

Safer Delivery Strategy

A team from University of Michigan Engineering and Michigan Medicine is exploring a different approach. In a study published in Advanced Materials, the researchers describe a nonviral delivery platform built from protein nanoparticles that successfully introduced genetic material into several human cell types, including liver cancer cells, kidney cells, and primary human T cells. The findings point to a potentially safer framework for gene delivery, particularly in settings where avoiding genomic disruption is critical.

How the Approach Stabilizes the Particles

The platform uses serum albumin, a natural blood protein, as the structural core of the nanoparticle. DNA or messenger RNA is encapsulated inside, and the particle surface is capped with a polycationic polymer through interfacial complexation rather than chemical cross-linking. That design gives the particles stability at physiological pH for up to 12 days and allows them to carry unusually dense nucleic acid payloads, ranging from 10% to 40% by weight. According to the the study, this corresponds to roughly 28 to 99 plasmids per particle.

In cell experiments, the nanoparticles were used to deliver genes encoding green fluorescent protein. Human liver cancer cells, kidney cells, and immune cells began to glow green after taking up and processing the particles, a proof-of-concept sign that the genetic cargo had been successfully released and expressed.

"There are a lot of diseases where a protein is missing or dysfunctional due to a single mutation, and we can definitely correct for that by introducing a new gene. Typically, this is done with viruses, but the viruses can be toxic and activate the immune cells. So there has been a push in the field to replace virus-based gene editing strategies," said Joerg Lahann, Professor of Chemical Engineering, director of the U-M Biointerfaces Institute and the corresponding author of the study.

How the Particles Are Manufactured

The particles are produced by electrohydrodynamic jetting, in which a mixture of protein and nucleic acid is accelerated through an electric field. As water rapidly evaporates, the protein condenses around the payload. Once cells engulf the particles, they enter endosomes. There, the positively charged surface polymer appears to create osmotic imbalance, drawing in water until the endosome ruptures and releases the cargo into the cell.

Mechanistically, the system performed well. The uptake efficiency exceeded 95%, and the particles entered cells through both macropinocytosis and clathrin-mediated endocytosis. The study also found an important optimization principle: when the total plasmid amount was held constant, increasing nanoparticle dosage was more effective than increasing payload density, producing a 1.6-fold improvement in transfection rate.

That finding may have practical implications for process design in cell therapy manufacturing, where efficiency, viability, and reproducibility all matter. Particularly encouraging was the performance in primary human T cells, a difficult target for nonviral delivery. The researchers report effective mRNA transfection while maintaining high cell viability, outperforming Lipofectamine MessengerMax in this setting.

Balancing Safety and Durability

The safety logic behind the approach is straightforward. Because the delivered plasmid DNA or mRNA does not integrate into the host genome, it should not break native genes the way integrating viral vectors sometimes can. The tradeoff is durability. mRNA persists for only days, and plasmid DNA for months at most. In some applications, that could mean repeated dosing. 

In others, the platform might serve as a transient but safer delivery vehicle. The authors also suggest that loading the particles with CRISPR-Cas9 components could eventually enable more durable correction with greater precision.

The platform could potentially be adapted for siRNA, antisense oligonucleotides, or Cas9-sgRNA complexes, and the protein shell itself could be altered to help direct the particles toward specific cell types.

For now, the work remains preclinical and proof-of-concept. But it addresses one of gene therapy’s most persistent engineering problems: how to deliver large nucleic acid cargo efficiently without paying the biological price of viral vectors. If the platform holds up in therapeutic models, it could help expand gene and cell therapies beyond the constraints of oncolitic viruses, electroporation, and other harsher delivery methods.

About Author: Hüseyin Kandemir

As a medical journalist with over 20 years of experience, I have served as an Editor and Reporter for various magazines, newspapers, and online broadcasting platforms, consistently demonstrating a strong commitment to excellence in journalism. My specialization includes medical science, digital health, AI for health, data science, and biotechnology.