https://www.science.org/content/blog-post/blasting-through-cells
I think that I can guarantee that you haven’t heard this phrase before: “ballistic microscopy”, the subject of this recent preprint. What the authors describe a combination of near-medieval technology on the one hand and cutting-edge analytical work on the other. They are bombarding cells with focused streams of gold nanoparticles (which range from 50 to 1000 nm diameter). These things are traveling at speeds up to 1 km/sec (over 2000 miles per hour (edit: fixed!)) and blast straight through their cellular targets. That’s a thickness of 2 to 4 microns for something like a HEK cell, and those velocities mean that the transit takes only a few picoseconds.
They come out the other side of the cell and splat into a hydrogel matrix on the other side. They’ve already slowed down a bit from their passage through the cell, and the hydrogel brings them to a halt. But when you examine them there, you find that they have carried along small amounts of the cellular material with them. It’s only a few attoliters, but by gosh that’s enough for current proteomic, nucleic acid, and cryo-EM techniques to get a handle on what’s in there. So what you get is an instantaneous snapshot of the cellular contents from a very small, very well defined needle-stick through a living cell. (People have actually done that, sampling cells with micro-needles and micro-straws, but this seems to be a step further).
You can tell that the authors are enjoying themselves: the technique itself is abbreviated BaM, and the hydrogel sample obtained is referred to as a “SPLAT-MAP”. (If that’s an acronym it seems to be undefined in the manuscript!) You get a lot of information from doing fluorescent imaging while the bombardment is underway - location of the particle stream hitting the cell (complete with streaks through the cytoplasm in high-speed side views), xy spatial distribution on the hydrogel itself, and depth (z) which is dependent on the size of the particles involved.
The group tested this in lysate from cells that had been expressing GFP-labled actin protein, and sure enough: the particles entrained fluorescent bits of cell material that corresponded to the labeled protein. And those particles penetrated less into the hydrogel braking material than control particles that were shot in directly, showing that they had experienced drag from schlorking through the cellular contents (my term, which all are welcome to if this technique catches on). Moving on to real cells, HEK293 cells were stained for nuclear membrane and cell membrane (to aid in IDing the now-fluorescent particles after capture), and they could be cultured right on top of the hydrogel surface.
If the fluorescent label was applied instead to another protein, then everything around that protein could be checked out. This was done with the known condensate-former CLIP170, and the nanoparticles pulled condensate droplets right out of the cell. Proteomic analysis showed 641 proteins (with a large number of them annotated as RNA binders, which fits with previous condensate work). One was keratin-18, which hadn’t been seen in these before but which seems to form filaments inside the droplets. But about 17% of them are unannotated, which is just the sort of thing you’d like to dredge up with a method like this.
Electron microscopy of the particles and their associated cellular samples showed that the cell contents that were brought along tended to be bunched up on the high-curvature edges of the gold particles (and not wetting the entire surface) and that they tended to be membrane-enclosed, sometimes with more than one membrane layer. There’s going to have to be more work done to interpret that, but it does seem significant (and might represent a type of sampling bias with this technique?)
There are a lot of things to be done in general! Zapping all sorts of cellular substructures, in both healthy and diseased or stressed cells, is an obvious set of experiments, and it’ll be interesting to see if some protein distribution maps can be produced from such runs. It’s certainly a new label-free assay technique, and I urge everyone interested in it to fire away and collect piles of data!
https://www.science.org/content/blog-post/blasting-through-cells
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icanhascheezburger_feed at 11:00am on 30/10/2025
