Scientists have developed a new method, combining cryo-electron microscopy, cryo-electron tomography, and image reconstruction, to visualize how nanomedicine particles interact with clusters of biomolecules.

Biomolecules operate in the living cell at the nanometer scale. A nanometer is a billionth of a meter—too small to be visualized by conventional microscopy. Nanomedicine, an application of nanotechnology aims to use nanoparticles as diagnostic and therapeutic interventions to detect and cure disease.

Medicines based on nanoparticles (NPs) promise to be more effective than current therapies while minimizing side effects. However, a lack of clear understanding as to how nanoparticles interact with biomolecules to exert a functional effect has limited the diagnostic and therapeutic use of these potentially lifesaving particles.

“There’s been a considerable investment of taxpayer money in cancer nanomedicine research, but that research hasn’t successfully translated to the clinic,” says Morteza Mahmoudi, PhD, assistant professor in the Department of Radiology and the Precision Health Program at Michigan State University. “The biological effects of nanoparticles, how the body interacts with nanoparticles, remain poorly understood. And they need to be considered in detail.”

Mahmoudi and his colleagues have introduced a unique combination of microscopic methods to enable more detailed consideration of those biological effects. These are reported in the article “Nanoscale characterization of the biomolecular corona by cryo-electron microscopy, cryo-electron tomography, and image simulation“published in the journal Nature Communications.

Biomolecules adhere to nanoparticles, creating a coating referred to as a corona (not to be confused with the novel coronavirus), the Latin word for crown. This biomolecular corona (BC) contains clues about how nanoparticles interact with a living system. The combinatorial imaging approach allows the researchers to see important differences between the coronas of polystyrene nanoparticles exposed to human plasma, the cell-free part of blood that contains biomolecules such as proteins, enzymes and antibodies.

This unprecedented view of the biomolecular corona is the first step to analyzing functional outcomes of the interaction of nanoparticular medicines and biological systems.

The biological identity of nanoparticles is established by their interactions with biomolecules on their surfaces after exposure to biological media. Understanding the nature of the biomolecular corona in its native state is, therefore, essential for its safe and efficient clinical application.

“For the first time, we can image the 3D-structure of the particles coated with biomolecules at the nano level,” says Mahmoudi. “This is a useful approach to get helpful and robust data for nanomedicines, to get the kind of data that can affect scientists’ decisions about the safety and efficacy of nanoparticles.”

The researchers observe that the coronas of nanoparticles from the same batch, exposed to the same human plasma, can provoke a variety of reactions at a single dose. Still, Mahmoudi believes these particles could shine as diagnostics tools instead of drugs.

Rather than trying to treat diseases with nanoscale medicine, he believes that nanoparticles would be well suited for the early detection of disease. For example, Mahmoudi’s group has previously shown this diagnostic potential for cancers and neurodegenerative diseases.

“We could become more proactive if we used nanoparticles as a diagnostic,” says Mahmoudi. “When you can detect disease at the earlier stages, it becomes easier to treat them.”

Although work like this ultimately helps move therapeutic nanomedicines into the clinic, Mahmoudi is not optimistic that broad approval will happen any time soon. There’s still much to learn about the biological impact of nanoparticles. Furthermore, minute variations in these tiny drugs can have a large difference in impact, the study underscores.

Earlier methods employed to analyze biomolecular coronas of nanoparticles such as differential scanning calorimetry (DSC), provide data limited to the thickness of corona, whereas the new approach reveals greater details of the physical characteristics of the corona including the dimensions of the molecular clusters and directional properties.

“Our findings demonstrate that the application of therapeutic NPs is more challenging than predicted in the published literature,” the authors note. “…Our findings also suggest that the employed combination of the electron microscopy techniques and image analysis can be used as a gold standard for defining the purity and homogeneity/heterogeneity of the biomolecular coronas at nanoscale resolution.”

This gold standard measurement can be used to establish the accuracy and reliability nanomedicines from proteomics and analytical chemistry data, as well as the suitability of various types of nanoparticles for clinical applications.

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