It’s happening on Twitter.
There is a Storify here to catch up.
I am looking for examples of convincing experimental demonstration of nanoparticles diffusing through membranes (if there are any). Please tweet your suggestions to #NPsCROSSmembranesYN or add in the comments sections of this post.
Rapha-z-lab 
You might find the work from Kostas Kostarelos interesting. Some years ago they have proposed that carbon nanotubes can “pierce through” cell membranes as a consequence, in part, of their aspect ratio. This hypothesis has been discussed in several papers published by his group and I am posting the link for one of their most recent work bellow. It contains some interesting TEM images a whole section on “passive diffusion”:
http://www.ncbi.nlm.nih.gov/pubmed/24056765
http://www.ncbi.nlm.nih.gov/pubmed/24056765
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Thanks Arthur! I am really looking forward to interesting discussions on this topic. I will email Kostas to ask whether he would write a guest blog.
Proposition 1. “because nanoparticles are “nano”, they can diffuse through the cell membrane”
Proposition 1, often read in papers and media (as a justification for why we should be particularly worried/excited) is false. You would just need one example of nanoparticles not diffusing through the cell membrane to demonstrate that it is false. There are tons of very solid evidence, over several decades, that the normal uptake mechanism for nanoparticles is endocytosis. [I often like to show the amazing EM pictures at the end of this 1957 paper ELECTRON MICROSCOPY OF HELA CELLS AFTER THE INGESTION OF COLLOIDAL GOLD ]
Proposition 2. “most nanoparticles do not, but some nanoparticles can, diffuse through the cell membrane”
Proposition 2 is not falsifiable. [As noted in the previous post, the equivalent of proposition 2 where you replace “nanoparticles” by “small molecules” is true; there are some small molecules that diffuse through membranes.] We need to break proposition 2 into more specific propositions; from a comment on the previous post, we have:
Proposition 2A: Zwitterionic quantum dots can diffuse through the cell membrane
Proposition 2B: Big mesoporous silica nanoparticles can diffuse through the cell membrane
Proposition 2C: Stripy nanoparticles can diffuse through the cell membrane
and from your comment above/Kostas’s work
Proposition 2D: Carbon Nanotubes can diffuse through the cell membrane
I’d like to focus on experimental evidence and ignore simulations at this stage.
Regarding proposition 2D, I have not looked at the entire body of work and I comment here only on this particular paper. To test these propositions, I think it is great (as is done here) to use simple model systems such as liposomes (although giant unilamellar vesicles combined with microscopy would be even better). Fig 4 reports some data on interactions of these CNTs with liposomes but what these data show is that there are some changes in the hydrophobic environment within the liposomes. It does not tell us anything about transport/diffusion across the membranes. The main body of evidence (apart from the simulation) is therefore Fig 5 and 6. What the authors are trying to do here is exceptionally difficult. Is there any possibility that these nanotubes have been moved during the sample preparation process? Would that explain why they are not in the same focal plane than the membrane itself? As a general comment not specifically targeted at this paper, I suggest we should change the current practice in the field and publish the entire sets of data (e.g. using figshare) rather than selected images.
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The interesting thing about the piercing theory is that it has been used to highlight the “bad” and the “good” from CNTs. On the one hand, there is the efficient delivery of cargos. This a quote from a collaborator from Kostas, for example””They can drill through cell membranes like tiny needles,” explains Alberto Bianco, “without damaging the cell.” If proteins or nucleic acids are attached to the nanotubes, they come right along through the membrane.” (http://www.chemeurope.com/en/news/49045/molecular-needles-carbon-nanotubes-inject-antimycotics-into-cells-and-increase-their-effectiveness.html)
On the other hand, the very same behaviour has been used to justify toxic effects. The idea was that if the CNT is too long, phagocytic cells try to engulf them without success, with the tubes piercing the cells and leading to a whole cascade of events and carcinogenic effects (like trying to eat a large salty stick that would pierce your cheeks!). This was termed “frustrated phagocytosis”. Figure 3B in the study bellow has yet another TEM image where CNT and membrane appear to be in the same focal plane: http://www.pnas.org/content/108/49/E1330.full .
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Well the hashtag didn’t catch on, but surely “convincing experimental demonstration of nanoparticles diffusing through membranes” can be found in the high resolution TEM images contained in Figure S2 from the Supporting Information of Van Lehn et. al. Effect of Particle Diameter and Surface Composition on the Spontaneous Fusion of Monolayer-Protected Gold Nanoparticles with Lipid Bilayers, Nano Lett, 2013, vol. 13 (9) pp. 4060-4067.
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A TEM image, even high resolution, cannot provide convincing experimental evidence of free diffusion through membranes (i.e. from one side to the other side of the bilayer) since it is a still picture.
What Fig S2 shows, convincingly, is that those nanoparticles get embedded in the membrane, i.e.most probably, there is an energetic gain for these to be in the membrane. This is great but absolutely not new. Nanoparticles have been used to stabilise emulsions for decades.
In the previous post, I wrote: “For an object to diffuse through the membrane, it would need to have no significant repulsive or attractive interactions with any of these components (otherwise it would be repelled and not go through, or attracted and then get stuck)”. The particles in the quoted paper most likely belong to the second category.
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