Cells and tissues have a multitude of methods for intercellular communication. Nanoscale assemblies that transfer proteins and RNAs between cells are known, but the impacts of external additions or synthetic materials is unclear.

Researchers from the University College of Dublin’s Centre for BioNano Interactions (CBNI) explored detailed changes in nanostructure-biological hybrid complexes as they leave one cell and enter another.

“We had long believed that there are natural couriers and gateways that allow special, very small particulates to communicate in organisms,” said lead author Kenneth Dawson, DPhil, CBNI director.

The team published their work in a paper titled, “Condensate corona–nanoparticle complexes transfer functional biomolecules between cells” in Nature Materials.

In rare instances, a subset of nanoparticles that enter a cell undergo an unexpected transformation, acquiring a coating known as a “condensate corona.” This corona allows for regulated entrance into the cell.

“By gaining access to these natural gateways, it could be possible to ferry ‘toolkits’ of functional biomolecules, for example, extended corrective messages, directly into previously inaccessible areas within cells, and across biological barriers, greatly improving the effectiveness and, importantly, the safety of RNA-, gene- and protein-based therapies,” said lead author associate professor Yan Yan, PhD, UCD School of Biomolecular and Biomedical Science.

Using “magnetic-cored, silica-shelled nanoparticles precoated with a grafted or adsorbed biomolecular corona,” the researchers created a scaffold that provided the cell with a recognition cue, allowing for the cells to deposit a secondary corona. With magnetic cores, and silica shells that carry fluorescent labels, the nanoparticles are easily controlled, extracted, and visualized.

Live-cell imaging showed that these additionally transformed nanoparticles were re-exported and retained both their original corona, along with their new cell-derived layer.

“By combining magnetic core extraction with an optimized pulse–chase regime and post-isolation washing, we obtained highly reproducible particle-complex isolates with minimal background contamination,” the authors wrote. Analysis showed that the cell-derived corona was “solid-like, structurally stable and biochemically robust.”

They also identified protein profiles using stable-isotope amino acid labelling (SILAC) in the cells producing the corona, followed by mass spec analysis. These proteins have a high affinity for the ER and mitochondria and about 70% of the proteins have been previously associated with mesoscopic intracellular RNA granules.

“With the prototype in our hands, we were able to break into these communications and understand how biological information is shared between cells. From there, we began to send our own messages via the same system,” Dawson noted.

In further tests, the team found that within endosomes of the recipient cell, the corona detaches from the core and the fates of the core and corona diverge, with the proteins and RNA components of the corona escaping the endosome—and escaping degradation—to be distributed within and access targets in the cell. They were able to disrupt this process and keep the corona and the attached materials, in the endosome by grafting short peptides onto the coronal surface.

Utilizing CRISPR-Cas9 they tested the functionality of corona-bound particles that escape the endosome. They generated particle complexes for bioluminescent markers to monitor functionality. Analysis revealed “intact enzymatic activity can be delivered to recipient cells by condensate-borne cargo.”

The authors explained that together, their data suggest these condensates function as an encoded biomolecular transfer program that are activated by the recipient cell. They wrote: “It is remarkable that such architectures, built entirely from endogenous biomolecules of producer cells, can embody transfer programs that overcome most of the challenges faced within nanoscale therapeutics.”

“The findings provide a new blueprint for sending strategic and therapeutically effective biological messages to currently inaccessible locations in the body. That points towards a new concept of medicine that could reverse, rather than manage, currently intractable diseases,” concluded Dawson.

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