in Figure 1A,B: (I) The NP reaches the membrane surface via diffusion. (II) The NP diffuses over the water–membrane interface
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.
Based on the values of the partition function as well as the difference in time scale between the leakage process and the entry process (seconds or minutes vs nanoseconds), we assume that a steady-state condition is rapidly reached. Therefore, by comparing eq 5 with eq 4, we find that
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.
c is a constant that depends on
How does it depends on these things? How can the authors compare experimental results to theory without explaining this information?
the GQD concentration inside the vesicle and the bilayer
"inside the bilayer" and "inside the vesicle" are two different things.
2 to 8
"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.
biolabeling
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.
wound disinfection
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.
cancer therapy
"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.
like drug delivery
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).
KD is estimated by using the approach outlined in ref
Why are the values of Kd not given anywhere in this paper?
Figure 9. Measured GQD leakage from different lipid vesicles. (A) Experimental images of photoluminescence change over a 1 h period. Images were taken every 15 min. White scale bar is 50 μm. (B) Photoluminescence intensity over a 1 h period for GQD-encapsulated vesicles with different lipid compositions is indicated. (C) Comparison of the model’s predictions to the permeability measured from experiment (error bars correspond to one standard deviation).
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?
KD of the NP in water/lipid as
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.
Specifically, a buckminsterfullerene, a curved OH-terminated graphene quantum dot (GQD), and GQD functionalized with two cysteine groups (cys-GQD) were used.(40) This selection covers NPs of similar size but different shape and hydrophilicity
So all of the intro (and title) is a general blurb about nanoparticles going through membranes, but these three examples are tiny hydrophobic objects.
ller nanoparticles can instead cross the membrane by passive transport, that is, by displacing, sometimes irreversibly, the lipids or by diffusing in the hydrophobic region of the membrane and then on the other side
This is an extraordinary assertion that is not backed up by references.
For particles with the smallest dimension larger than the membrane thickness, approximately above 10–15 nm, the permeation is generally controlled by membrane deformation(23) and endocytosis.(24)
This gives the impression that particles generally permeate. This is contradiction with earlier statements that correctly indicate that they don't.
an effective barrier. Nonetheless,
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).
ensing of cellular behavior.(6−10)
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.
led release,(3,5)
See above... https://hyp.is/ZNoJet4FEemMLa-NmPW_Eg/pubs.acs.org/doi/10.1021/acsnano.9b03434
such as drug delivery,(2−4)
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".
are especially frustrating in biomedicine. Indeed, recently, there has been a blooming of applications
Is it just me or is there a disconnect, even a contradiction between "especially frustrating" and "blooming of applications"?
However, this is not the case for most macromolecules, such as proteins or nanoparticles (NPs), whose hydrophilicity and large size hamper direct diffusion through the membrane lipid bilayer.(1)
Exactly. Nanoparticles large size and hydrophilicity hamper direct diffusion through the membrane bylayer. So far so good.
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