Well... This is the opposite of what ref 21 says!!! Again, see this quote from ref 21:

Despite the widespread use of protease-specific peptide cleavage (11), little is known about the determinants of the efficacy of VC-based ADCs. Here, we report an analysis of VC linker-based ADCs. We found that removal of cathepsin B did not affect the activity of ADCs and that proteases other than cathepsin B can also cleave the VC linker with varying degrees of efficiency. In addition, we show that alternative mechanisms could account for ADC efficacy independent of linker cleavage by proteases.

and in fact Fig S7 shows increases for all proteases; the main difference is in the saturation value reached and not in the kinetics, which does not suggest specificity.

unclear

Despite the widespread use of protease-specific peptide cleavage (11), little is known about the determinants of the efficacy of VC-based ADCs. Here, we report an analysis of VC linker-based ADCs. We found that removal of cathepsin B did not affect the activity of ADCs and that proteases other than cathepsin B can also cleave the VC linker with varying degrees of efficiency. In addition, we show that alternative mechanisms could account for ADC efficacy independent of linker cleavage by proteases. Our data can help inform the design of ADCs and have implications about the possible mechanisms of ADC resistance.

From ref 21... so this reference is rather pointing to the fact that protease-based linkers targeting cathepsins are not specific

"active" is not the same as "differentially expressed" and even "differentially expressed" might not be enough to ensure cell specificity...

Achieving a high degree of endosomal escape is already challenging, but the ambition here is higher: to do so with cell specificity...

This is a strange argument. I thought cathepsins were precisely major enzymes involved in protein degradation.

I am struggling to understand this table. There are 6 rats in each group. If the total number of nodules is 110 for the DEN group, then the average should be 110/6 = 18.3, not 58.78! Where does this number comes from? In fact these average number of modules don't make sense. For example, for the last line, it is impossible to 9.98 by averaging 6 positive integers. The closest to 10 you could get would be by having 10, 10, 10, 10, 10 and 9, average 9.83.

12 were used for the tox study, now, now it is 5 groups of six. 30 + 12 = 42 yet it was announced that 36 rats were used.

group 1, control, nothing at all done

group 2, DEN-induced cancer, then nothing

group 3 is treated with silymarin which is presented as "a standard drug" but which it isn't. Instead, it is "a standardized extract of the milk thistle seeds" according to this wikipedia page and it is a natural product which is described as having hepatoprotective properties against drug induced injuries (https://www.medscape.com/viewarticle/422884) ; which is very different from an anticancer drug.

group 4, DEN, then Ag NPs at a dose of 20 mg/kg

group 5, DEN, then Ag NPs at a dose of 30 mg/kg

Oral tox study 4 x 3 = 12 rats 0, 20, 30, 50 mg/kg

No reference.

reference?

the automatically generated link confirms that this is not the right word; I guess the authors (?) meant "induction"?

"novel" compared to what? The definition in the previous sentence encompasses any molecules (or larger entities) that has anticancer properties

so, basically, any source

This sentences is not really understandable. Alternative to what?

compared to what?

Why?

Whilst there are a couple of research articles on "Carissa carandas" and "hepatic cancer", there is no "use in hepatic cancer", i.e. there are no clinical application.

"Hepatic cancer [...] remain asymptomatic diseases." This is absurd. First sentence of the abstract. Has anyone read this?

J'applaudis fortement... mais je suis obligé de déclarer un conflit d’intérêt : je me suis impliqué fortement dans ce type d’activités depuis plus de dix ans et c'est même maintenant en partie mon domaine de recherche.

Comment l'y contraindre ou tout au moins l'y inciter fortement?

Un forum tel que PubPeer est né précisément de l'incapacité (ou plus exactement du manque de volonté) des revues de participer aux processus de correction de la science.

Quelles particules? Est-on en train de suggérer que cette observation est générale et applicable a toutes les particules? (ref 70 => zinc oxyde)

Qu'est ce que cela veut dire?

Le dioxyde de titane est utilise en crème solaire mais on développe des méthodes pour décontaminer la peau en cas de contamination accidentelle? Je ne comprend pas.

L’étude en question s'est focalisée sur ces deux récepteurs. Il parait donc difficile de conclure que les effets observés sont particuliers à ces molécules?

Lesquelles?

Lesquelles?

En quoi l'accumulation dans le foie est une indication de franchissement de barrières biologiques? N'est-ce pas justement sa fonction?

Lesquelles?

Qui est ce "elles"? Les nanoparticules en général?

Important effectivement

Peut-être parce ce que le problème est mal pose? Ou que l’hypothèse de départ (une spécificité nano dans la toxicologie) est incorrecte?

Exagération de l'inconnu. On sait beaucoup de choses sur les "nanoparticules" qui s'appelaient colloides avant de s'appeler nanoparticules.

That criterion is open to bias, especially if there are differences of intensity.

This does not say if the curves are for the patch or the beams, nor to what extent it is robust and reproducible.

I find it quite hard to understand exactly what has been done from this figure.

This is the first article we are going to discuss in 3DbioNet's online journal club. https://twitter.com/3DbioNet/status/1244670405534679040

The article is about a 3D model of cardiac tissue using 3D bioprinting of rat cells ("neonatal rat ventricular cardiomyocytes"). The hope/promise is applications in heart transplantation (how realistic is that?) and in vitro "modeling" (for testing cardiac toxicity of drugs?).

The 3D system was in a patch form or a string form.

Is that really the best proof of principle available?

Nice experiment. Slightly philosophical point maybe, but does "rescuing activity" (which would occur without doing anything in a normal animal, these particles) really "exogeneous targeting".

This is quite strange. One would expect that removing the receptor would reduce binding, but here the main effect seems to be not on binding to the membrane but to uptake.

80% silencing with LNPs

The presentation in Fig 1c is relative to no ApoE. It gives the impression that iLNP is hugely better that cLNP but that is not the case as 1b shows.

This "article" is in fact an advertorial, i.e. paid for content. It looks like a scientific article but is not peer reviewed. And it does not include declarations of conflict of interest even though the first author is a founder of a company that develop therapies based on the technology advertised in this feature.

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?

what the hell is this? I would assume 100% by definition.

"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.

Nothing to do with interactions of NPs with membranes.

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.

it is a liposome for delivery to the liver...

First, we knew. Second, there was disinformation campaigns by powerful lobbies. Third, the analogy does not work because smoking or asbestos are two well-defined products whose dangerosity can be evaluated. The same cannot be said of "nanoparticles" - the question itself is ill posed. Maybe there is a lobby of the titanium dioxide in the food industry that try actively to prevent us from seeing the toxicity. If so, it must be aggressively investigated. What I see more is poor science and poor journalism that lump things together to create confusion and fear.

Again, this is deeply misleading. It gives the impression that there is something really new with all this nanotech engineering happening in the past two decades... and then talks about silicon dioxide which has been used for many more than two decades. I very much doubt that its formulation has changed much in the meantime. Here is a 1986 review "Food applications and the toxicological and nutritional implications of amorphous silicon dioxide." The difference: they use the word "colloid" (appears 19 times in the article) rather than "nanoparticle" (nowhere to be seen - but it is the same). https://www.ncbi.nlm.nih.gov/pubmed/3011357

It is completely false and misleading to describe nanoparticle food additives as "engineered to almost atomic scale". These are crude polydisperse materials which for most have been in use for a long time, long before the word "nanoparticle" became fashionable.

That review is actually much much more balanced than what this sentence suggests. Notably it includes the fact that the human body has been exposed to nanoparticles for millions of years and has mechanisms to deal with it, and the fact that nanoparticles can be beneficial or toxc... in other words, the fact that they are nanoparticles does not tell us much about potential toxicity.

These examples are listed to make a general point about "nanoparticles" but they bring together two different materials, various routes of exposure, etc and simplify everything. This is absurd as can be shown by the following thought experiment: imagine the same paragraph about "molecules" lumping together drinking benzene, water and too much alcohool. Surely you would have to conclude that the unintended effects of water are something to be very wary of.

What does this mean? Nanoparticles are certainly not a technology. Even Nanotechnology is not "a technology".

This sentence really shows the absurdity of the situation. The exposition of children to candies, chewing gums and desserts is an enormous and undisputed health problem, documented, leading to huge costs and suffering. Here however the panic is about the non-demonstration of an absence of risks.

Again... there IS a concern if a small body eats lots of candy. There is absolutely no doubt of that. I suppose if fear of nanoparticles reduce ingestion of candies we might see a health benefit.

Well exactly: it is complete nonsense. So why exactly are we doing this?

It is not a new technology. First, what is "it"? Nanoparticles? Their use in food? If so, as noted above, we are talking at least half a century (for the examples in this article) or millenia depending exactly on the definition. Second, it is not "a technology".

There is really no lack of research on silver toxicity.

Really? "minute size" compared to what? What is the proportion that translocates? How does it compare to other potentially toxic agents such as dangerous small molecules?

Not sure what is meant by this sentence, but none of those references have anything to do with smartflares.

See above. This is a considerable misunderstanding of the Smartflare technology: the gold is not supposed to stay where the mRNA was. In fact, to address this 'problem', Mirkin (the inventor of the SmartFlare) even developed another version where the mRNA stay bound to the mRNA (the famous stickyflare).

The SmartFlares are supposed to enable the measurement of mRNA levels in cells. Nobody has ever claimed that they can target mRNA, even less so target specific cells on the basis of their mRNA levels. There is no reason to believe that the amount of gold in different cells should correlate with the amount of mRNA. In fact the working principle of the sensor assumes that all cells uptake the same amount of SmartFlare but the fluorescence levels are different depending on the amount of mRNA because of the release of a reporter strand from the nanoparticle. [the technology does not work, but that is another story]

Reference 12 does not show this at all. There are no in vivo experiments nor any experiments with tissues (as the title indicates).

Reference 3 does not include any study of passive diffusion through membranes. To the contrary, it includes a liposomal transfection agent to help oligonucleotide-capped nanoparticles go inside cells. Reference 14 does not mention passive diffusion whatsoever. It is an article about active transport (endocytosis and exocytosis). Reference 15 includes the sentence "GNPs smaller than 30 nm are leaving the cell again by passive diffusion (15)" (that's right, identical word for word)... where (15) is reference 14 above.