The problem is often not the therapeutic gene itself, but how to deliver it. The brain is protected by multiple biological barriers that prevent most circulating molecules from entering brain tissue and reaching the intended targets. For Jingjing Gao, a biomedical engineer at the University of Massachusetts Amherst, tackling this challenge became a natural extension of her scientific journey. Trained as a chemical engineer, Gao’s doctoral research focused on designing novel materials capable of controlled drug release.
During her postdoctoral training, however, she became increasingly interested in translating these technologies to real-world disease applications. Collaborations with clinicians working on traumatic brain injury, Alzheimer’s disease, and other neurological disorders convinced her that delivery — not necessarily the therapeutic molecules themselves — was often the factor limiting progress.
Today, Gao leads a laboratory developing nonviral, nanoparticle-based platforms designed to transport genetic medicines across biological barriers and into specific brain cells. By combining materials engineering, drug delivery, and neuroscience, her team aims to build a toolbox of technologies that could help unlock the full potential of gene therapies for CNS diseases.
Why is delivering gene therapies to the brain so challenging?
The brain is an extremely protected organ. When people think about brain delivery, they often focus on the blood-brain barrier, and for good reason. If a therapy is administered intravenously, it first must cross this highly intricate barrier, which blocks almost 99 percent of biomolecules and many other compounds from entering the brain.
But crossing the blood-brain barrier is only the first challenge. Once a therapeutic reaches the brain, it still needs to navigate a highly compartmentalized environment. Different brain regions control different functions, so therapies often need to reach specific areas, such as the cortex or hippocampus. Beyond that, they may need to target a particular cell type, such as neurons, while avoiding others.
These multiple levels of targeting are what determine whether a therapy will be effective and safe. In the brain, even small off-target effects can have significant consequences. Precision delivery is therefore critical. There are several ways to administer therapies, including intravenous, intrathecal, local, and nose-to-brain delivery. Each route presents its own barriers, and understanding how to overcome them is a major focus of our work.
Why are viral vectors still widely used for brain gene delivery, and what are their limitations?
The first advantage of viral vectors is their transfection efficiency. Viruses naturally evolved to deliver genetic material into cells, so they are exceptionally effective at doing so. That is why many of the gene therapies currently approved by the FDA use viral vectors.
However, viral vectors also have disadvantages. Production costs are high, and immunogenicity remains a major concern. Some patients may already have pre-existing immunity to certain viral components, and immune responses can create serious safety risks.
Another challenge is that viral vectors cannot currently be administered repeatedly because immune reactions become more likely after initial exposure.
What advantages could nanoparticles offer over viral vectors?
Safety, in the first place. No matter how much engineering you have done on viral vectors, there are still safety issues to worry about. With nanoparticles, you can use many different materials, but they are nonviral. Lipid nanoparticles, for example, use lipid components that are essentially components of cell membranes. From a manufacturing perspective, this can also make the process much easier and cheaper, and the materials are easier to scale up for industrial applications. There are also many chemistries you can work with to design different materials and tune their properties to reduce toxicity.
Of course, limitations remain. Their delivery efficiency is not yet comparable to viral vectors. Researchers also need to address tissue tropism and how to direct nanoparticles to specific organs, although this is a challenge shared with viral vectors.
How is your laboratory developing a “toolbox” for brain delivery?
Our lab focuses on the delivery problem itself. We study different administration routes and ask what types of materials can overcome the barriers associated with each route. We focus on chemically tuning materials to help them cross these barriers. We create libraries of chemically distinct nanoparticles and collaborate with other teams to screen them in animal models and human organoid systems. We then evaluate where those particles go and how efficiently they reach the brain and validate whether promising candidates can deliver therapeutic cargo and actually produce an effect.
This approach allows us to generate many candidates with the potential to deliver cargo to different brain cells. We have completed intravenous screening studies and developed a separate library for nose-to-brain delivery. We are now following up on promising candidates, optimizing their brain accumulation based on their chemical properties, and investigating whether we can tune their specificity toward different cell types.
What are the most exciting challenges your group is currently tackling?
One of the areas we are most excited about is cell-specific targeting. Crossing the blood-brain barrier is important, but ultimately, we want nanoparticles to reach the exact cells involved in a disease. We are developing sequential targeting strategies that first target endothelial cells at the blood-brain barrier to cross it and then target the specific cell types we’re interested in within the brain.
We are also collaborating with researchers who specialize in technologies such as focused ultrasound and magnetic-field-based approaches. The idea is to combine physical tuning with chemical tuning. By integrating both strategies, we hope to achieve a much higher level of precision.
Do you think nonviral systems will eventually replace viral vectors for brain gene therapy?
I firmly believe that will happen someday. Many researchers are working in that direction, and it is certainly one of our goals as well. We can learn a great deal from viral vectors and apply many of those principles to material design.
The biggest hurdles for nanoparticles today involve intracellular delivery. Once inside a cell, nanoparticles often become trapped in endosomes and are eventually degraded in lysosomes. Improving endosomal escape is therefore a major focus across the field. Another challenge is nuclear delivery. For DNA-based therapeutics, the genetic cargo must reach the nucleus, and this is particularly difficult in nondividing cells. Designing nanoparticles that can overcome these two major barriers will likely be among the most important challenges to address over the longer term.
How do you see the future of brain-targeted gene therapy?
I think the field is very promising. But success will require close collaboration across disciplines. Researchers studying neurobiology, fundamental biology, drug delivery, and drug development all bring different expertise and perspectives. Bringing those fields together will be essential for translating promising discoveries into effective therapies.
