Scientists identify ‘bottleneck’ in drug delivery pathways in stem cells
In order to gain entry to a cell, nanoparticles can be engulfed by the membrane surrounding the cell, forming bubble-like vesicles—endocytosis. Credit: Adapted from CC BY-SA 4.0

Our bodies have evolved formidable barriers to protect themselves against foreign substances, from our skin to our cells and every component within the cells. These defenses pose a challenge for pharmaceutical drugs and therapies that have to overcome multiple obstacles to reach their targets.

Barriers are important in pharmaceutical science and drug design, but they are still unknown and how to overcome them is a mystery.

The delivery of drugs to cells can be difficult and a recent study sheds some light on why.

Coming past obstacles.

Hundreds of millions of us have been injected with the COVID-19 vaccine, which has to be enclosed in protective bubbles so that it can pass through the body's defenses and reach the intended target.

Stem cells, immune cells, and nerve cells have barriers that are difficult to overcome, so the delivery of particles into these cells is even more difficult.

The researchers combined cutting-edge microscopy techniques to track the delivery of nanoparticles, which are often used for drug delivery.

According to their findings, certain types of cells prevent nanoparticles from reaching their intended target by trapping them inside bubble-like vesicles.

A mathematical model that can predict how efficient the delivery of nanoparticles into cells will be was created by the team.

The delivery process of particles into cells has been broken down so that we can see how the cells protect themselves.

Quantitative understanding of how parts of the cell and nanoparticles interact is needed to design improved delivery methods. If you were to design an airplane, you would have to analyze the aerodynamics of each part before you build it.

Our findings will pave the way for more tailored and innovative therapies that use tailored delivery for individual patients.

It's out for delivery.

Because of the small scale, it has been difficult to image the delivery of nanoparticles in cells. The multidisciplinary team was able to come up with innovative ways to overcome these hurdles. They combined two different types of analysis to study the whole delivery process.

In real-time, we were able to see the movement of the nanoparticles across the barriers and into each compartment.

The team identified the critical stage that prevents delivery of the nanoparticles to their cell targets by modifying each step of the process.

In order to get into a cell, nanoparticles need to be covered by the cell's outer shell. The particles would escape from the bubbles in the cell. The stem cells used in this study seem to have a problem with the nanoparticles getting trapped inside of them. They can't get to their target because they can't enter the cell.

The researchers combine their observations and analysis in a mathematical model that can predict how quickly particles will enter a cell

Predicting the concentration of the nanoparticles in a cell can be done with our model.

To better understand the delivery mechanisms used to pass into cells, different types of nanoparticles and cells can be incorporated. Predicting how well the COVID-19 vaccines will deliver messenger RNA into a cell is an example.

The ability to map out the different components and inner workings that make up the delivery pathways leads to understanding how to control these pathways. Some really exciting things could be opened up by this.

We hope that our new tools and understanding have created an initial foothold for the system, from where we, and other researchers, can begin climbing and begin exploring.

More information: Xuan Yang et al, Probing the Intracellular Delivery of Nanoparticles into Hard-to-Transfect Cells, ACS Nano (2022). DOI: 10.1021/acsnano.1c07648 Journal information: ACS Nano