In fact, in the simulation a potential is applied to drive the particles towards the membrane so neither (I) nor (II) can be described as free diffusion.

These words are confusing. If they assume that I(t) is proportional to [GDQ]m then equations 4 and 5 are simply identical with two different notations. I can see no reasonable reason to assume that though.

How does it depends on these things? How can the authors compare experimental results to theory without explaining this information?

"inside the bilayer" and "inside the vesicle" are two different things.

"2 to 8 nm" is a huge range given; the range covered by figure 5 does not extend beyond 2.5 nm. One can guess that the probability of a low density lipid fluctuation extending over 8 nm is essentially zero.

Ref 6 (2013) does not demonstrate wide use in biolabelling. It is a synthesis and proof of principle paper. 6 years later, no biologist are using these materials for their imaging needs. However there are tons more of papers about the "emerging" carbon nanomaterials for imaging. The paper has a figure about uptake in cells. It says nothing about the mechanisms of uptake and it is not possible to conclude from the data provided.

Carbonaceous NPs are not widely used in wound disinfection. This 2014 paper propose the idea and doing experiments on bacteria and on mice. It contains very little about interaction of the NPs with cells.

"widely used in cancer therapy" I know that this kind of poetic license is common in scientific writing but it is nevertheless wrong. Carbonaceous NPs have not been used in cancer therapy. Those two references are materials synthesis papers that claim that they could be used in the future for this purpose. Reference 5 is about pegylated graphene oxide which is fundamentally different from anything modelled here (and the PEG is to make it water soluble). Reference 5 also concludes the nanoparticles enter by endocytosis.

Reference 2 is a paper about micron-size particles that can be opened by ultrasounds. It does not have any experiments with membranes nor living things. Reference 3 is mostly a materials synthesis and characterization paper. The little it has about interaction with cells, figure 8 and 9, concludes unambiguously that the particles enter by endocytosis, i.e. nothing to do with the kind of mechanisms modelled in this paper. Reference 4 is about particles which are ~75 nm diameter so very different from the materials modelled in this paper. Like for Ref 3, the paper concludes unambiguously that entry into the cells is by endocytosis (that's even visible from TOC visual abstract).

Why are the values of Kd not given anywhere in this paper?

The partition coefficient tell us that it should be 100% in the membrane (see table 1). Why don't we see any accumulation in the membranes at all?

Isn't it lipid/water rather than water/lipid? I strongly suspect it is given that in the table Pt is given as 100% for all three "nanoparticles" and C60 has a very high oil/water (eg Kd toluene water ~7.

So all of the intro (and title) is a general blurb about nanoparticles going through membranes, but these three examples are tiny hydrophobic objects.

This is an extraordinary assertion that is not backed up by references.

This gives the impression that particles generally permeate. This is contradiction with earlier statements that correctly indicate that they don't.

That apparent contradiction is missing a crucial point. What is the proportion of material getting "cytoplasmic access"? The Cell Penetrating Peptides field is a right mess. One thing is sure: most (maybe all) CPPs enter via endocytotic pathways and for any CPP only a tiny proportion reaches the cytosol. My own experience with the TAT-HA2 peptide was not particularly encouraging. Importantly, when "access to the cytosol" is measured by a biological outcome (e.g. transfection or toxicity), this can be achieved by a rare event. In other words, depending on the conditions, efficient transfection (e.g. 75% of cells transfected) can be achieved with very low percentage of particles reaching the cytosol (e.g. 99.9% in endosomes; 0.1% escape).

Again, all of these papers are chemistry papers describing the synthesis of new materials which, according to their authors, could be useful for deep tissue imaging etc. Some of these are 5+ years old. These are indeed examples of "engineering for applications" but not of applications. Essentially no biologists use these materials for their imaging or sensing needs.

See above... https://hyp.is/ZNoJet4FEemMLa-NmPW_Eg/pubs.acs.org/doi/10.1021/acsnano.9b03434

It enables engineering for applications... But it does not enable applications. None of these examples of drug delivery are remotely realistic. These are examples of chemistry papers not of drug delivery applications. The first paper (ref 2) is so far from drug delivery application that it does not even have cell culture experiments (not to mention preclinical or clinical work). Ref 3-4 are also mostly materials synthesis/characterization papers ; they do have some cell uptake/toxicity experiments. Still million miles away from "applications in drug delivery".

Is it just me or is there a disconnect, even a contradiction between "especially frustrating" and "blooming of applications"?

Exactly. Nanoparticles large size and hydrophilicity hamper direct diffusion through the membrane bylayer. So far so good.

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