Surface Modification of Metallic Nanoparticles for Targeting Drugs
Round 1
Reviewer 1 Report
Strange division under the table of contents. The review consists of two sections: 1 - Introduction and original sections equal in meaning to it; 2 - Conclusion, which is more like a regular original section, since the conclusion should contain more general conclusions.
If to expand with references, the Summary section is more suitable for the Introduction, and, conversely, the Introduction section is more suitable for the Summary.
There are few references for review.
The review does not contain also data on magnetic metal nanoparticles, which also assume magnetic properties. On the basis of the latter, contrast agents for MRI are being developed, as well as therapeutic methods for selectively influencing cancer cells inside the Gantry by heating them in vivo above the temperature of protein denaturalization by a radiofrequency magnetic field.
Author Response
Thank you so much for your feedback. Below I submitted all the edits across both reviews. I put it in table format due to the major changes and extensive overhaul that needed to be done for simplicity and your convenience. I labelled each point as it pertains to each reviewer.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Y. Pathak and team presented a review entitled “Surface Modification of Metallic Nanoparticles for Targeting Drugs.” The authors discussed the surface modification strategies of metallic nanoparticles, including polymer coating, functionalization with specific functional groups, and targeting ligands. The team also offered a glimpse of several challenges that must be addressed for their successful clinical translation.
Overall, the manuscript was not elaborately written. Hence, we recommend a detailed revision addressing the following concerns and suggestions carefully to reach more audiences and readers of different disciplines before considering a possible publication.
1. The authors must give their affiliations.
2. We recommend that the authors include figures describing metallic nanoparticles' surface modification strategies. For example, the authors can compile nucleic acid coating (siRNA, miRNA, mRNA, etc.), targeting ligands (aptamers, cyclic RGD), and polymer coating (PEG, chitosan, dextran sulfate, etc.) onto metal nanoparticles.
3. Redundant phrases with abbreviations or acronyms were observed. They will increase the word count but not the scientific information. Abbreviate or acronym after their first appearance in the manuscript.
Lines 168, 212: poly(lactic-co-glycolic acid) (PLGA)
4. Abbreviations or acronyms must be included after their first appearance in the manuscript. However, the authors did not follow this fundamental rule, which makes the readers uncomfortable.
For example, in Line 179 central nervous system was introduced without its abbreviation of CNS. Line 196, shown CNS.
Line 130. EPR
Line 292: enhanced permeability and retention (EPR)
5. No abbreviations or acronyms are required if the scientific information is given only once in the manuscript. These abbreviations only increase the word count without scientific information.
For example,
Line 169. LDL
Line 191. BDNF
Line 204. GI
6. Expand the full forms of abbreviations or acronyms.
For example,
Line 133. siRNA --> small interfering RNA (siRNA)
Line 133. miRNA --> microRNA (miRNA)
7. Various biologics were surface coated onto the metallic nanoparticles. We highly recommend that the authors introduce the following suggestions in the correct place of the manuscript.
(A) Single-stranded DNA was adsorbed by citrate-capped gold nanoparticles (AuNPs), resulting in increased AuNP stability, which forms the basis of several biochemical and analytical applications (Langmuir 2012;28(8):3896-902).
(B) Freezing accelerated the adsorption of thiolated DNA strands onto AuNPs (Langmuir 2019;35(19):6476-6482).
(C) Fluorescently-labeled DNA oligonucleotides were adsorbed onto iron oxide nanoparticles via the backbone phosphate and quench fluorescence. Arsenate ions exchange adsorbed DNA to increase fluorescence, allowing the detection of arsenate down to 300 nM (Chem Commun (Camb) 2014;50(62):8568-70)
(D) Spherical nucleic acids (SNAs):
SNAs are three-dimensional nanostructures consisting of nucleic acids that are densely functionalized and oriented spherically around a nanoparticle core. SNA enters the cells more rapidly and in higher quantities without the use of transfection agents by engaging scavenger receptors that facilitate caveolin-mediated endocytosis than that of its analogous, one-dimensional strands of the same sequence. These SNA are used for miRNA profiling (J Am Chem Soc 2012;134(3):1376-91), detection of mRNA in living cells using SNA-based NanoFlare constructs (Anal Chem 2012;84(4):2062-6), and immunostimulation or immunoregulation by engaging TLRs (Proc Natl Acad Sci U S A 2019;116(21):10473-10481).
8. In the abstract, the authors claimed that their manuscript discussed several challenges associated with their clinical translation of metallic nanoparticles. However, minimal discussion was provided. This is the most crucial section for introducing the author’s perspectives on next-generation coating strategies to overcome the challenges and barriers of clinical translation.
(a) Accumulation of metal nanoparticles in the scavenger cells of the reticuloendothelial system organs, particularly the liver, is one of the biggest hurdles to clinical translation because it decreases the delivery of a sufficient dose of nanoparticles to the pathological site and often raises the toxicity and immunogenicity (Nat Mater 2016;15(11):1212-1221). The extracellular domains of scavenger receptors, the professional phagocytic pattern recognition receptors, which are highly expressed on macrophages, recognize the dextran-coated superparamagnetic iron oxide nanoparticle conjugates (Feridex) (Bioconjug Chem 2012;23(5):1003-9) through various nano-bio interactions (Adv Drug Deliv Rev 2023;198:114895). Transient saturation of RES cells by commercial liposome (NanoToday 2015; 10(1):11-21), stiff nanogel (Nat Commun2023;14(1):1437), and in situ stealth coating of liver scavenger wall cells by two-arm-PEG-oligopetide (Sci Adv 2020;6(26):eabb8133) substantially prevented the blood clearance of nanoparticles, thereby increasing tumor accumulation.
(b) Endosomal entrapment of siRNA-coated metal nanoparticles hampers the maximized gene silencing activity. To overcome this issue, hydroxychloroquine (HCQ) was conjugated onto the surface of siRNA-coated gold nanoparticles functionalized with PEG for enhanced endosomal escape (Biomaterials 2016;90:62-71).
9. Are there any FDA/EMA-approved metal nanoparticles? Discussion regarding this direction would encourage the readers to research metal nanoparticles. Please confirm the following formulations are metal nanoparticles before tabulating them.
a) Approval of Hensify®/NBTXR3 (a 50 nm crystalline hafnium oxide HfO2 nanoparticle with negatively charged phosphate coating), a selective radio-enhancer for high energy deposition in the tumor only when exposed to ionizing radiations (on/off activity), is a revolutionary approach for the local treatment of solid tumors. This HfO2 nanoparticle was approved by the USFDA in 2019 in combination with radiotherapy with and without cetuximab for treating advanced head and neck squamous cell carcinoma.
b) NanoTherm® is an aminosilane-coated superparamagnetic iron oxide nanoparticle (hydrodynamic diameter ~15 nm) (SPION), that was approved by EMA in 2010 for intra-tumoral injection for the treatment of recurrent glioblastoma multiforme, pancreatic and prostate cancer.
c) Feridex®/Endorem® (SPION) was approved by FDA in 1996 as an MRI agent for observing liver/spleen lesions.
d) Ferumoxtran-10/Combidex®/Sinerem® (ultra-small SPION) was approved in 2005 by FDA and Holland as an imaging agent for lymph node metastases.
e) GastroMARK™/Umirem®/Ferumoxsil (SPION) was approved by FDA in 2009 as an MRI contrast media for imaging the delineation of the bowel from other organs and tissues.
f) Resovist®/Cliavist®/ Ferucarbotran (US-SPION) was approved by EMA in 2011 as a contrast-enhanced MRI agent for liver lesions.
Author Response
Thank you so much for your feedback. Below I submitted all the edits across both reviews. I put it in table format due to the major changes and extensive overhaul that needed to be done for simplicity and your convenience. I labelled each point as it pertains to each reviewer.
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
In the future, pay more attention to contrast agents in MRI
Author Response
We greatly appreciate your expert insights and the time you've invested in reviewing our manuscript. Your comment about paying closer attention to contrast agents in MRI is particularly interesting. Could you kindly elaborate on how you envision this aspect fitting into the scope of our current manuscript ? Additionally, do you have further recommendations that could make our review excel and be more beneficial to the scientific community?
Your expertise is invaluable to us, and we look forward to your additional guidance.
Author Response File: 
Author Response.docx
Reviewer 2 Report
Y. Pathak and team presented a review entitled “Surface Modification of Metallic Nanoparticles for Targeting Drugs.” The authors discussed the surface modification strategies of metallic nanoparticles, including polymer coating, functionalization with specific functional groups, and targeting ligands.
The authors incorporated the reviewer’s suggestions and comments, ranging from challenges associated with the clinical translation of metal nanoparticles to FDA-approved metal nanoparticles. However, they failed to insert the accurate references suggested by the reviewer. We believe a good review always introduces the original articles along with previously published reviews. It seems the authors mostly cited the previously published reviews.
1. Page 2, Line 51: Please introduce what is a Gantry.
For example, Gantry, a special device that can usually irradiate tumors at 360 degrees.
2. Page 10, Line 314: Signal regulatory protein α (SIRPα) is not a scavenger receptor.
Hence, we recommend the authors change the following sentence.
“To further reduce scavenger receptor binding” (change to) à “To further reduce the macrophagic scavenger cell recognition.”
3. Page 10, Line 305-325: Accurate references were necessary. Please revisit the previous suggestions of the reviewer for precise references about the newly added information.
(a) Several original articles were suggested by the reviewer regarding RES accumulation through scavenger receptor recognition and preconditioning strategies, including transient oversaturation of liver cells by first injection of commercial liposomes and in situ stealth coating of liver scavenger wall cells by two-armed PEG. These RES blockading strategies have shown reduced RES uptake of nanoparticles. Please revisit the original suggestions of the reviewer.
(b) Please cite the reference that conjugated the hydroxychloroquine (an endosomal escape-enhancing agent) onto the surface of siRNA-coated gold nanoparticles for enhanced endosomal escape.
4. Line 508-608: References were listed without appropriate numbers.
Author Response
Thank you for the thorough review and valuable comments that have significantly contributed to improving the quality of our manuscript. We have diligently addressed each point you raised, and we believe that the revisions have strengthened the paper.
I look forward to any other corrections or possible suggestions to further strengthen the paper.
Author Response File: Author Response.docx
