Nanomedicine-Based Advances in Brain Cancer Treatment—A Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

There are a huge number of reviews on the topic of treating brain tumors using nanotechnology. For example, I have read or reviewed over the past few years - 10.1016/j.addr.2022.114115, 10.1016/j.semcancer.2022.06.011, 10.3390/pharmaceutics14051048, 10.1080/17425247.2024.2347320, etc. (no need to quote, this is for illustration). All reviews are quite similar, some are written and illustrated a little better, some a little worse. How is this review better than what has already been written? What is the advantage of this review over others?

The problem of borrowing. For example, "Table 2. Comparison of Conventional and Nanomedicine Strategies for Brain Cancer Treatment" - data from section 7.2.2 Targeted therapy of article 17 presented in the form of a table. "Table 3. Nanomedicine Strategies Targeting the Tumor Microenvironment" is a compilation of two papers 29 and 30. "Table 4. QD: Types, associated toxicity concerns and clinical translational potential" is a compilation of papers 85 and 86. And so on. Probably there is nothing that cannot be fixed, but it looks a little strange. Perhaps additional styling of the text is needed... 

The authors introduce a lot of abbreviations, some of which are not generally accepted, some of which are used in the text only a few times. For example, PAMAM, NvIH, PAMPA, etc. The abbreviations mpa (Mercaptopropionic Acid) and PA (Photoacoustic) and PEI (Polyethyleneimine) are not used. The abbreviation ROS is not deciphered at all. This makes it very difficult to read the text. Please check everything again and use abbreviations only in cases of multiple repetition (10 times or more). Unify, for example, write all the names of nanoparticles in the same way, otherwise in the text zinc oxide nanoparticles are written as ZnO-NPs, and gold as AuNPs.

Section 4 of the manuscript is devoted to listing nanoobjects that can be used as a carrier in the treatment of brain tumors. It remains completely unclear to me why these classes of carrier nanoparticles are listed. Why did the authors list these nanoparticles and, for example, did not list nanoparticles based on iron or iron oxide in a graphene-like shell? Where are the silicate nanoparticles? Where are the nanoparticles based on amorphous carbon? The authors will say that it is impossible to embrace the immensity, I agree. Then why is Section 4 of the manuscript needed?

Section 5 of the manuscript is simply a continuation of Section 4 of the manuscript with the introduction of a new taxonomy of nanoobjects. Why is this necessary?

The authors write that modifications of the surface of NPs with ligands (peptides, antibodies, and aptamers) provide site-specific interaction with transport systems through the BBB. This is a key point in the logic of constructing the review, and this point is not disclosed in any way. Later it turns out that the review manuscript has point 6. BBB penetration strategies using nanotechnology. Obviously, the order of the narrative in the manuscript needs to be changed. At the very least, the points need to be swapped. It also seems to me that the review lacks a table or figure describing the currently used mechanisms for overcoming the BBB.

In Section 7. Nanotheranostics: Integrating Diagnosis and Therapy, the authors move on to disclosing the theranostic approach. Quite interesting. I would like to share my opinion that 7.1.3.2 AuNPs for Fluorescence Enhancement is written very mysteriously. Moreover, gold nanoparticles do not fluoresce. For some reason, Section 7 does not have a subchapter on targeted radiotherapy of tumors, although it is already used in the clinic... The authors need to add a corresponding section.

Sections 8-11 are written quite clearly, although not always in an orderly manner.
Positive features: Current topic, High-quality illustrations, modern literature, there is a section on prospects and limitations.
Negative features: Low degree of novelty, Low degree of generalization of known facts, low degree of orderliness, problems with abbreviations.

Overall, the review is too early to publish...

Author Response

Manuscript Title: Nanomedicine-Based Advances in Brain Cancer Treatment – A Review
Journal: Neuroglia
Manuscript ID: neuroglia-3656461

We sincerely thank the reviewers for their time and thoughtful comments. Below, we address each point raised, organized according to the individual reviewers

Response to Reviewer 1 comments:

Query (Q)1: There are a huge number of reviews on the topic of treating brain tumours using nanotechnology. For example, I have read or reviewed over the past few years - 10.1016/j.addr.2022.114115, 10.1016/j.semcancer.2022.06.011, 10.3390/pharmaceutics14051048, 10.1080/17425247.2024.2347320, etc. (no need to quote, this is for illustration). All reviews are quite similar, some are written and illustrated a little better, some a little worse. How is this review better than what has already been written? What is the advantage of this review over others?

Response (R) 1: We appreciate this critical question. To clearly distinguish our review, we revised the Introduction and Future Perspectives sections to explicitly highlight our contributions, including: (i) comprehensive discussion of combined therapeutic and diagnostic nanotechnologies (nanotheranostics), (ii) inclusion of cutting-edge advancements such as artificial intelligence-guided nanoparticle design, CRISPR-based nanoparticle strategies, and RNA-based nano-delivery methods, (iii) emphasis on immunotherapy and personalized medicine approaches in nanomedicine, and (iv) inclusion of recent literature up to April 2025. These elements collectively set our review apart and provide novel insights into the rapidly evolving field.

Q2: The problem of borrowing. For example, "Table 2. Comparison of Conventional and Nanomedicine Strategies for Brain Cancer Treatment" - data from section 7.2.2 Targeted therapy of article 17 presented in the form of a table. "Table 3. Nanomedicine Strategies Targeting the Tumor Microenvironment" is a compilation of two papers 29 and 30. "Table 4. QD: Types, associated toxicity concerns and clinical translational potential" is a compilation of papers 85 and 86. And so on. Probably there is nothing that cannot be fixed, but it looks a little strange. Perhaps additional styling of the text is needed... 

R2: Tables 2, 3, and 4 in the previous version, 5 in the current version have been rewritten entirely to reflect original interpretations based on multiple sources. The revised tables focus on comparative mechanisms, applications, and limitations, rather than direct compilations. Table titles and legends were also refined to ensure clarity and distinction from previously published content.

Q3: The authors introduce a lot of abbreviations, some of which are not generally accepted, some of which are used in the text only a few times. For example, PAMAM, NvIH, PAMPA, etc. The abbreviations mpa (Mercaptopropionic Acid) and PA (Photoacoustic) and PEI (Polyethyleneimine) are not used. The abbreviation ROS is not deciphered at all. This makes it very difficult to read the text. Please check everything again and use abbreviations only in cases of multiple repetition (10 times or more). Unify, for example, write all the names of nanoparticles in the same way, otherwise in the text zinc oxide nanoparticles are written as ZnO-NPs, and gold as AuNPs.

R3: We agree with this comment and have meticulously reviewed all abbreviations. Rarely used abbreviations have been removed entirely and all remaining abbreviations are explicitly defined at first mention. Furthermore, nanoparticle terminology (e.g., ZnONPs, AuNPs) has been standardized, and a comprehensive abbreviation list has been provided at the manuscript's end for clarity.

Q4: Section 4 of the manuscript is devoted to listing nanoobjects that can be used as a carrier in the treatment of brain tumors. It remains completely unclear to me why these classes of carrier nanoparticles are listed. Why did the authors list these nanoparticles and, for example, did not list nanoparticles based on iron or iron oxide in a graphene-like shell? Where are the silicate nanoparticles? Where are the nanoparticles based on amorphous carbon? The authors will say that it is impossible to embrace the immensity, I agree. Then why is Section 4 of the manuscript needed?

R4: We appreciate this valuable suggestion. Section 4 has been extensively revised to incorporate silicate nanoparticles, iron oxide–graphene hybrids, and amorphous carbon-based systems such as graphene oxide and carbon dots. An introductory explanation now outlines their selection, based on the clinical relevance and scientific potential.

Q5: Section 5 of the manuscript is simply a continuation of Section 4 of the manuscript with the introduction of a new taxonomy of nanoobjects. Why is this necessary?

R5: We recognize the need for clarity and have restructured these sections to distinctly differentiate their contents. Section 4 now exclusively addresses therapeutic nanocarriers, while Section 5 is dedicated to diagnostic and biosensing applications. Clear introductory statements have been added to Section 5 to underline this differentiation.

Q6: The authors write that modifications of the surface of NPs with ligands (peptides, antibodies, and aptamers) provide site-specific interaction with transport systems through the BBB. This is a key point in the logic of constructing the review, and this point is not disclosed in any way. Later it turns out that the review manuscript has point 6. BBB penetration strategies using nanotechnology. Obviously, the order of the narrative in the manuscript needs to be changed. At the very least, the points need to be swapped. It also seems to me that the review lacks a table or figure describing the currently used mechanisms for overcoming the BBB.

R6: We have significantly reorganized the manuscript for improved logical flow, positioning Section 6 earlier in the narrative. Detailed descriptions of ligand-based transport mechanisms for BBB penetration have been expanded, complemented by Figure 2, a schematic illustration summarizing key strategies to enhance understanding.

Q7: In Section 7 Nanotheranostics: Integrating Diagnosis and Therapy, the authors move on to disclosing the theranostic approach. Quite interesting. I would like to share my opinion that 7.1.3.2 AuNPs for Fluorescence Enhancement is written very mysteriously. Moreover, gold nanoparticles do not fluoresce. For some reason, Section 7 does not have a subchapter on targeted radiotherapy of tumors, although it is already used in the clinic... The authors need to add a corresponding section.

R7: We thank the reviewer for pointing out this critical issue. We corrected the text in Section 7.1.3.2, clarifying that gold nanoparticles enhance fluorescence through surface plasmon resonance effects rather than intrinsic fluorescence. Additionally, we introduced a dedicated subsection (7.3) addressing targeted radiotherapy using nanoparticle platforms.

Q8: Sections 8-11 are written quite clearly, although not always in an orderly manner.
Positive features: Current topic, High-quality illustrations, modern literature, there is a section on prospects and limitations.
Negative features: Low degree of novelty, Low degree of generalization of known facts, low degree of orderliness, problems with abbreviations.

R8: Following this valuable recommendation, Sections 8 through 11 have been systematically reorganized. Subheadings were refined, and explicit transitional statements were included to enhance logical progression and coherence throughout the manuscript.

Q9: Overall, the review is too early to publish...

R9: We appreciate the reviewer's candid assessment. All major points highlighted, including originality, structural coherence, clarity of abbreviations, and completeness of content, have been thoroughly addressed. We believe these substantial revisions now render the manuscript ready for reconsideration.

Reviewer 2 Report

Comments and Suggestions for Authors

The review paper on the use of nanoparticles in the treatment of CNS tumors is a very extensive and detailed study. It is well written, in understandable language. The authors treat the subject in a multi-threaded manner, from the pathogenesis of CNS tumors, to the characteristics and application of various types of nanoparticles, to the future prospects of this type of therapy. The whole is enriched by tables and figures. The manuscript is a mine of knowledge about nanoparticles.

I have two comments:
1) Methodology: The authors describe in detail the criteria for inclusion and exclusion of articles, but I miss a flowchart that would present how many articles met the initial criteria, how many and why were rejected from the analysis, and how many were finally included in the review.
2) In such extensive articles, it is worth considering including a table of contents of the chapters.

Author Response

Manuscript Title: Nanomedicine-Based Advances in Brain Cancer Treatment – A Review
Journal: Neuroglia
Manuscript ID: neuroglia-3656461

We sincerely thank the reviewers for their time and thoughtful comments. Below, we address each point raised, organized according to the individual reviewers

Reviewer 2

Q1: The review paper on the use of nanoparticles in the treatment of CNS tumors is a very extensive and detailed study. It is well written, in understandable language. The authors treat the subject in a multi-threaded manner, from the pathogenesis of CNS tumors, to the characteristics and application of various types of nanoparticles, to the future prospects of this type of therapy. The whole is enriched by tables and figures. The manuscript is a mine of knowledge about nanoparticles.

R1: We sincerely thank you for your generous and thoughtful evaluation of our manuscript. Your recognition of its clarity, comprehensive coverage, and structural organization is truly appreciated. We are grateful for your encouraging words regarding the multi-layered approach and informative illustrations. Your feedback has reinforced our effort to provide a well-structured and insightful contribution to the field of nanomedicine in CNS tumor therapy.

Q2: Methodology: The authors describe in detail the criteria for inclusion and exclusion of articles, but I miss a flowchart that would present how many articles met the initial criteria, how many and why were rejected from the analysis, and how many were finally included in the review.

R2: We thank the reviewer for raising this important concern. As this manuscript is a narrative rather than a systematic review, we agree that the presence of a detailed methodology was misleading. Therefore, we have removed the methodology section entirely to maintain consistency with narrative review conventions. We appreciate this constructive feedback which significantly improves manuscript clarity.

Q3:  In such extensive articles, it is worth considering including a table of contents of the chapters.

R3: We appreciate this helpful suggestion. A comprehensive table of contents has been created and included before the Introduction section in the manuscript.

We trust that these detailed revisions effectively address all reviewer concerns and substantially improve the manuscript's clarity, originality, and scientific rigor. We remain grateful for the insightful suggestions provided by both reviewers.

Sincerely,
Dr. Sivakumar Vijayaraghavalu
(On behalf of all co-authors)
Corresponding Author
Department of Life Sciences, Manipur University
drshiva@manipuruniv.ac.in

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I hope I helped the authors improve the manuscript.