Nanoparticles as Strategies for Modulating the Host’s Response in Periodontitis Treatment

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The author did a good job compiling the literature regarding the strategies for modulating the host`s response in periodontitis. However, there are a few points that may be revised.

Title:
Since it is a revision, consider removing the word "new" from the title. 

Figure 1:
It is not the focus of the manuscript, consider removing and adding new figures to illustrate each mechanism of action of the presented therapies.  Elaborate to show readers the therapeutic targets and possibly the mechanism of action.

Main text:

Add a table and summarize the potential benefits of the therapies and present clinical data when available.

Conclusion:
It needs revision to make it more concise. 

 

Author Response

For review article

Response to Reviewer 1 Comments
1. Summary
Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted in the re-submitted files.
2. Questions for General Evaluation	Reviewer’s Evaluation	Response and Revisions
Is the work a significant contribution to the field?		Thank you for appreciating our article as a significant one.
Is the work well organized and comprehensively described?		We are thankful for you appreciation.
Is the work scientifically sound and not misleading?		We are thankful for you appreciation.
Are there appropriate and adequate references to related and previous work?		Thank you for your kind appreciation of our reference list.
Is the English used correct and readable?		Thank you for giving us such a significant mark on our English language.
3. Point-by-point response to Comments and Suggestions for Authors
Comments 1: Since it is a revision, consider removing the word "new" from the title.
Response 1: [Type your response here and mark your revisions in red] Thank you for pointing this out. We agree with this comment. Therefore, we have removed ‘new’’ from the title of our article. The change can be found on page 1, paragraph 1, line 2.
Comments 2: Figure 1: It is not the focus of the manuscript, consider removing and adding new figures to illustrate each mechanism of action of the presented therapies.  Elaborate to show readers the therapeutic targets and possibly the mechanism of action.
Response 2: Thank you for your valuable suggestion. We have incorporated two new figures and a table to enhance the clarity of our discussion.   Figure 1, titled "Effects of the Most Used Metal Nanoparticles in Periodontology," has been added on page 6, paragraph 1, lines 206-207. Figure 2, titled "Nanotherapeutics in Periodontal Treatment Plans," is now included on page 12, paragraph 2, lines 447-448. Table 1, titled "Nanoparticles as Local Antimicrobial Means in Periodontal Therapy," has been included on page 11, paragraph 2, lines 426-427. This table provides examples of commercially available products, detailing their mechanisms of action, application forms, and biodegradability. We appreciate your insightful feedback, which has helped improve the comprehensiveness of our manuscript. Please let us know if any further adjustments are required.
5. Additional clarifications
We sincerely appreciate your thoughtful and constructive feedback, which has helped us enhance the clarity and comprehensiveness of our manuscript.

 

 

 

Reviewer 2 Report

Comments and Suggestions for Authors

This review highlights nanotechnology's potential in therapy and the need for structured treatment plans to improve oral and systemic health.

Fix grammar and structural issues (e.g., singular/plural agreement, spelling errors).

Introduction

The introduction mentions "chronic disease" multiple times in similar contexts (e.g., "Periodontitis is a chronic inflammatory disease" and "Periodontitis is a chronic disease that impacts approximately 11% of the global population").

2.

The section emphasizes benefits but does not address the limitations or risks of nanotechnology in dentistry.

Table 1 is not cited in the text and is very brief. Could you add more types of nanoparticles with references to it?

2.1

The font is in italics.

2.2

Adding a brief sentence or two discussing these limitations would balance the discussion.

2.3

Table 2 is not cited in text.

There is no mention of cytotoxicity, nanoparticle accumulation risks, or regulatory challenges.

Presents nanoparticles as superior to antibiotics without discussing possible bacterial adaptation over time.

"with its antimicrobial properties" → should be "with their antimicrobial properties"

"boosting the cell proliferation" should be "boosting cell proliferation"

The passage ends abruptly without summarizing key findings or implications.

The table at the end of the section is not numbered, and more details related to studies with references would be beneficial.

2.4

"Photothermal therapy (PTT) and photodynamic therapy (PDT) has a lower risk of inducing resistance…" Correction: "Photothermal therapy (PTT) and photodynamic therapy (PDT) have a lower risk…"

The passage presents PTT and PDT as superior to antibiotics but does not mention their challenges.

The mechanism of Cu+ oxidation is not clearly linked to antimicrobial effects.

Add a critical discussion on the limitations of light-based therapies (depth penetration, tissue damage, oxygen dependency).

2.5

The abrupt introduction of macrophage polarization makes the transition between general immune responses and specific cellular mechanisms feel disconnected. Add a transition sentence: "Given the immune system's role in periodontitis progression, researchers have focused on modulating macrophage activity to control inflammation and promote tissue regeneration."

"The hosts immune response" → should be "the host's immune response"

"Some essential blood cell such as macrophages" → should be "Some essential blood cells, such as macrophages,"

3.

Briefly explain why these markers are important (e.g., "RUNX2 is essential for osteoblast differentiation, and ALP and COL-I are key indicators of bone formation.").

The potential drawbacks of Au NPs are not discussed, making the passage one-sided.

4.

The phrase "eliminating all bacteria" is misleading, as antibiotics and PDT may reduce bacteria rather than completely eliminate them.

Include potential limitations of probiotics and nano-antibacterial therapies. For example, there are challenges in maintaining probiotic viability in nano-delivery systems. Risk of unintended microbial imbalances—introducing probiotics without proper microbial ecology assessment may lead to the overgrowth of other species.

5.

The benefits of nano-delivery systems are highlighted, but their challenges are ignored.

For example, add a balanced perspective: "While nano-delivery systems show potential for managing periodontitis in patients with comorbidities, challenges such as nanoparticle safety, regulatory approval, and cost-effectiveness must be addressed before widespread clinical application."

Finish the section like this: "Future nanotherapeutic strategies are expected to address local periodontal damage and systemic complications. However, further research is needed to optimize safety, efficacy, and large-scale clinical applications."

6

Figure 1 is not mentioned in the text.

The section presents natural compounds as promising but does not compare their effectiveness to traditional treatments (e.g., antibiotics, NSAIDs, or nanotechnology-based antibacterial approaches).

Missing Aspects:

How do these natural compounds compare in efficacy to conventional treatments?

Are they effective alone, or do they work best as adjuncts to other therapies?

What are the ideal concentrations/dosages needed for efficacy in humans?

For example, While natural compounds like quercetin and resveratrol have demonstrated strong anti-inflammatory effects, their efficacy compared to conventional antibiotics and NSAIDs remains under investigation. In many cases, they may serve best as adjunctive therapies rather than standalone treatments."

 

"Quercetin possess a defensive effect." Correction: "Quercetin possesses a defensive effect."

The passage introduces nano-drug delivery systems only in the final sentence, without explaining how they improve natural compound efficacy. For example, "To overcome these challenges, researchers are developing nano-drug delivery systems, such as liposomes, polymeric nanoparticles, and hydrogels, to improve the bioavailability and stability of natural compounds. These nano-systems enable targeted delivery to periodontal tissues, enhancing therapeutic outcomes while minimizing systemic side effects. Future studies will focus on optimizing these nano-formulations for clinical application in periodontitis treatment."

Conclusion

The conclusion focuses heavily on the promise of nano-therapeutics but does not sufficiently discuss challenges. For example, "Despite their potential, challenges such as regulatory approval, large-scale production, and long-term safety must be addressed before widespread clinical implementation."

The conclusion ends abruptly after listing systemic diseases without a final summarizing thought. Example "As research advances, integrating nano-therapeutic approaches with precision medicine could transform periodontitis management, improving both oral and systemic health outcomes."

 

Comments on the Quality of English Language

The manuscript requires a thorough grammatical and spelling check.

Author Response

Response to Reviewer 2 Comments

 

Point-by-point response to Comments and Suggestions for Authors

 

 

Comments 1: Fix grammar and structural issues (e.g., singular/plural agreement, spelling errors).

 

Introduction

 

The introduction mentions "chronic disease" multiple times in similar contexts (e.g., "Periodontitis is a chronic inflammatory disease" and "Periodontitis is a chronic disease that impacts approximately 11% of the global population").

 

Response 1: Thank you for pointing this out. We strongly agree with this comment. We have removed the term ‘chronic’ from the 3rd sentence in the Introduction section. This change can be found on page 1, Introduction section, line 28.

 

Comments 2: The section emphasizes benefits but does not address the limitations or risks of nanotechnology in dentistry. Table 1 is not cited in the text and is very brief. Could you add more types of nanoparticles with references to it?

 

Response 2: We agree with this very relevant remark. We have, accordingly, modified the discussion section to emphasize this point.

 

In response to your feedback, we have cited Table 1 in the text with the following statement: "The main characteristics of some nanoparticles are represented in Table 1." This addition can be found on page 3, paragraph 4, lines 122-123.

 

Additionally, to provide a more comprehensive discussion on the challenges and considerations associated with nanotechnology, we have expanded the Discussion section. The limitations of nanotechnology applications are now highlighted in detail in this section, which has been added as an additional part of the article and is located on pages 12-13, lines 449-504.

 

We greatly appreciate your valuable feedback and the opportunity to enhance our manuscript.

 

Comments 3: The font is in italics.

 

Response 3: We fully agree with this insightful remark. To address this, we have standardized the font across all paragraphs to ensure consistency throughout the manuscript. We sincerely appreciate your attention to detail and apologize for this unintentional oversight. Thank you for bringing it to our attention!

 

Comments 4:

2.2

Adding a brief sentence or two discussing these limitations would balance the discussion.

 

Response 4: We appreciate this valuable remark. To address it, we have included the limitations in both the Discussion and Conclusion sections, which can be found on pages 12–14. These additions provide a more comprehensive overview of the challenges and considerations related to nanotechnology in periodontal therapy. Thank you for your insightful feedback!

 

Comments 5: Table 2 is not cited in text.

There is no mention of cytotoxicity, nanoparticle accumulation risks, or regulatory challenges.

Presents nanoparticles as superior to antibiotics without discussing possible bacterial adaptation over time.

"with its antimicrobial properties" → should be "with their antimicrobial properties"

"boosting the cell proliferation" should be "boosting cell proliferation"

The passage ends abruptly without summarizing key findings or implications.

The table at the end of the section is not numbered, and more details related to studies with references would be beneficial.

 

Response 5: We agree with this very remark. We have added an additional sentence including the table. The changes can be found on page 5, last paragraph, lines 214 and 215.

All grammar remarks are corrected!

We have included the negative impacts of nanoparticles in both the Discussion and Conclusion sections, which can be found on pages 12–14. These additions provide a more comprehensive overview of the challenges and considerations related to nanotechnology in periodontal therapy.

 

Comments 6:

2.4

"Photothermal therapy (PTT) and photodynamic therapy (PDT) has a lower risk of inducing resistance…" Correction: "Photothermal therapy (PTT) and photodynamic therapy (PDT) have a lower risk…"

The passage presents PTT and PDT as superior to antibiotics but does not mention their challenges.

The mechanism of Cu+ oxidation is not clearly linked to antimicrobial effects.

Add a critical discussion on the limitations of light-based therapies (depth penetration, tissue damage, oxygen dependency).

 

Response 6: We agree with this very remark. The changes can be found on page 6, paragraph 4, line 230.

We appreciate your thoughtful suggestion. In response, we have added a Discussion section to provide critical remarks and a broader perspective on the topic. This addition ensures a more comprehensive and balanced analysis.

 

Comments 6:

2.5

The abrupt introduction of macrophage polarization makes the transition between general immune responses and specific cellular mechanisms feel disconnected. Add a transition sentence: "Given the immune system's role in periodontitis progression, researchers have focused on modulating macrophage activity to control inflammation and promote tissue regeneration."

"The hosts immune response" → should be "the host's immune response"

"Some essential blood cell such as macrophages" → should be "Some essential blood cells, such as macrophages,"

 

Response 6: Thank you for pointing this out for us, We consider this remark very signifficant.

The changes can be found on page 7, paragraph 3, lines 265-267.

We have rephrased multiple paragraphs to ensure clarity and provide a more precise and coherent meaning.

 

 

 

Comments 7:

4.

The phrase "eliminating all bacteria" is misleading, as antibiotics and PDT may reduce bacteria rather than completely eliminate them.

Include potential limitations of probiotics and nano-antibacterial therapies. For example, there are challenges in maintaining probiotic viability in nano-delivery systems. Risk of unintended microbial imbalances—introducing probiotics without proper microbial ecology assessment may lead to the overgrowth of other species.

 

Response 7: Thank you for this very significant remark. We have replaced the incorrect term ‘eliminating’ with the suggested correct term ‘reducing’.

The change can be found on page 9, paragraph 2 , line 342.

 

Comments 8:

5.

The benefits of nano-delivery systems are highlighted, but their challenges are ignored.

For example, add a balanced perspective: "While nano-delivery systems show potential for managing periodontitis in patients with comorbidities, challenges such as nanoparticle safety, regulatory approval, and cost-effectiveness must be addressed before widespread clinical application."

Finish the section like this: "Future nanotherapeutic strategies are expected to address local periodontal damage and systemic complications. However, further research is needed to optimize safety, efficacy, and large-scale clinical applications."

 

Response 8: We strongly appreciate the recommendations, that is why we have included them as additional paragraph. The addition can be found on page 10, paragraph 1, lines 389-394.

 

Comments 9:

6

Figure 1 is not mentioned in the text.

The section presents natural compounds as promising but does not compare their effectiveness to traditional treatments (e.g., antibiotics, NSAIDs, or nanotechnology-based antibacterial approaches).

Missing Aspects:

How do these natural compounds compare in efficacy to conventional treatments?

Are they effective alone, or do they work best as adjuncts to other therapies?

What are the ideal concentrations/dosages needed for efficacy in humans?

For example, While natural compounds like quercetin and resveratrol have demonstrated strong anti-inflammatory effects, their efficacy compared to conventional antibiotics and NSAIDs remains under investigation. In many cases, they may serve best as adjunctive therapies rather than standalone treatments."

"Quercetin possess a defensive effect." Correction: "Quercetin possesses a defensive effect."

The passage introduces nano-drug delivery systems only in the final sentence, without explaining how they improve natural compound efficacy. For example, "To overcome these challenges, researchers are developing nano-drug delivery systems, such as liposomes, polymeric nanoparticles, and hydrogels, to improve the bioavailability and stability of natural compounds. These nano-systems enable targeted delivery to periodontal tissues, enhancing therapeutic outcomes while minimizing systemic side effects. Future studies will focus on optimizing these nano-formulations for clinical application in periodontitis treatment."

 

Response 9: Thank you for this out for us.

We appreciate your feedback regarding the figures. In response, we have removed the original figure and added two new ones that better align with the context of the manuscript. We believe these changes enhance both clarity and relevance.

 

Comments 10:

Conclusion

The conclusion focuses heavily on the promise of nano-therapeutics but does not sufficiently discuss challenges. For example, "Despite their potential, challenges such as regulatory approval, large-scale production, and long-term safety must be addressed before widespread clinical implementation."

The conclusion ends abruptly after listing systemic diseases without a final summarizing thought. Example "As research advances, integrating nano-therapeutic approaches with precision medicine could transform periodontitis management, improving both oral and systemic health outcomes."

 

Response 10: We strongly agree with this remark. Accordingly, we have added a Discussion section and modified the Conclusion section to provide a more robust and comprehensive tone throughout the manuscript. Thank you for your valuable feedback.

 

We sincerely appreciate the insightful and constructive remarks provided by the reviewers. Their valuable feedback has helped us refine our manuscript, ensuring greater clarity, coherence, and scientific rigor. In response to the suggestions, we have made significant revisions, including the addition of a Discussion section to critically analyze the implications of our findings, as well as modifications to the Conclusion to strengthen the overall message of the study. Furthermore, we have incorporated new figures and a table to enhance the presentation of key concepts.

 

We believe these improvements have contributed to a more comprehensive and well-structured manuscript. Once again, we extend our gratitude to the reviewers for their thoughtful comments and the opportunity to improve our work. We hope that the revised version meets the expected standards and adds valuable insights to the field of periodontology and nanotherapeutics.

Reviewer 3 Report

Comments and Suggestions for Authors

This review attempts to synthesize current literature on nanoparticle-based therapeutic approaches for periodontitis treatment. While the topic of nanotechnology in periodontology is relevant, the manuscript fails to present any significant novel insights. The content largely reiterates established knowledge rather than offering a critical synthesis or unique perspective. Many of the cited applications of nanoparticles in drug delivery, antimicrobial therapy, and host modulation are well-documented in prior reviews. The manuscript lacks an in-depth discussion of unresolved challenges, emerging trends, or gaps in research that could direct future investigations. Without a clear thesis or original analysis, the review does not advance the field beyond existing literature.

Narrative reviews are the lowest tier of the evidence pyramid and lack the rigor of systematic reviews or meta-analyses. To be publishable, it needs major revisions, including a clearer focus on research gaps, a stronger evidence-based discussion, and significant language improvements. Without these, the review does not offer sufficient academic value.

Comments on the Quality of English Language

The manuscript has frequent grammatical errors, awkward phrasing, and unclear sentence structures, making it difficult to read. Issues include incorrect subject-verb agreement, article usage, and redundancy. The structure is also weak, with loosely connected sentences and excessive repetition. The writing needs to be more precise, concise, and logically organized.

Author Response

For review article

Response to Reviewer X Comments
1. Summary
Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted files. [This is only a recommended summary. Please feel free to adjust it. We do suggest maintaining a neutral tone and thanking the reviewers for their contribution although the comments may be negative or off-target. If you disagree with the reviewer's comments please include any concerns you may have in the letter to the Academic Editor.]
2. Questions for General Evaluation	Reviewer’s Evaluation	Response and Revisions
Is the work a significant contribution to the field?		After our revision, we sincerely hope that you will consider our manuscript a valuable contribution to the field.
Is the work well organized and comprehensively described?		We have made significant revisions to the structure of our manuscript in the hope of enhancing its overall quality.
Is the work scientifically sound and not misleading?		We have made significant revisions to the structure of our manuscript in the hope of enhancing its overall quality.
Are there appropriate and adequate references to related and previous work?		Thank you for your appreciation of the references we have included.
Is the English used correct and readable?		We have made significant corrections to grammatical, spelling, and linguistic issues in the manuscript, aiming to enhance its readability.
3. Point-by-point response to Comments and Suggestions for Authors
Comments 1: [This review attempts to synthesize current literature on nanoparticle-based therapeutic approaches for periodontitis treatment. While the topic of nanotechnology in periodontology is relevant, the manuscript fails to present any significant novel insights. The content largely reiterates established knowledge rather than offering a critical synthesis or unique perspective. Many of the cited applications of nanoparticles in drug delivery, antimicrobial therapy, and host modulation are well-documented in prior reviews. The manuscript lacks an in-depth discussion of unresolved challenges, emerging trends, or gaps in research that could direct future investigations. Without a clear thesis or original analysis, the review does not advance the field beyond existing literature.   Narrative reviews are the lowest tier of the evidence pyramid and lack the rigor of systematic reviews or meta-analyses. To be publishable, it needs major revisions, including a clearer focus on research gaps, a stronger evidence-based discussion, and significant language improvements. Without these, the review does not offer sufficient academic value.]
Response 1: Thank you for your detailed and constructive feedback. We truly appreciate the time and effort you have invested in reviewing our manuscript.   In response to your comments, we have made significant revisions to improve the clarity, depth, and originality of our review. Specifically, we have:   Enhanced the Critical Discussion – We have added a comprehensive discussion section (pages 12–14) that critically examines unresolved challenges, emerging trends, and research gaps in nanoparticle-based therapies for periodontitis. This aims to provide a forward-looking perspective and highlight areas that require further investigation.   Strengthened the Thesis and Novel Insights – Instead of reiterating well-documented findings, we have restructured the manuscript to emphasize the latest advancements and unique aspects of nano-based approaches. We now provide a clearer framework for future research directions, differentiating our work from previous reviews.   Refined the Language and Readability – We have carefully revised the manuscript for linguistic accuracy and coherence, ensuring a more polished and professional presentation.   Expanded the Discussion on Research Gaps – We have incorporated additional analysis of the limitations and challenges in the field, offering a more balanced and critical synthesis rather than merely summarizing existing literature.   We sincerely hope that these substantial improvements address your concerns and elevate the manuscript’s academic value. We believe the revised version now makes a meaningful contribution to the field and respectfully ask for your reconsideration.   Thank you again for your insightful remarks, which have greatly contributed to the refinement of our work.
Comments 2: [The manuscript has frequent grammatical errors, awkward phrasing, and unclear sentence structures, making it difficult to read. Issues include incorrect subject-verb agreement, article usage, and redundancy. The structure is also weak, with loosely connected sentences and excessive repetition. The writing needs to be more precise, concise, and logically organized.]
Response 2: Agree. In response to your comments, we have carefully revised the manuscript to enhance its grammatical accuracy, readability, and overall clarity. We have addressed issues related to subject-verb agreement, article usage, and redundancy. Additionally, we have improved phrasing to ensure more precise and concise writing.   Regarding the structure, we have carefully reviewed the organization of the manuscript and made refinements where necessary. However, we believe that the overall structure effectively conveys the key concepts and scientific findings. The revised version now presents the information in a logically connected and cohesive manner while maintaining a clear and structured narrative.   We hope that these significant revisions enhance the manuscript’s quality and clarity. Thank you again for your valuable input, which has greatly contributed to improving our work.
4. Response to Comments on the Quality of English Language
Point 1:
Response 1 We have made significant corrections to grammatical, spelling, and linguistic issues in the manuscript, aiming to enhance its readability.
5. Additional clarifications
Dear Reviewer,   We sincerely appreciate your detailed and constructive feedback. Your comments have been invaluable in helping us improve the quality and clarity of our manuscript.   In response to your concerns regarding language and structure, we have conducted a thorough revision of the manuscript. This includes significant grammatical corrections, refinement of sentence structures for clarity, and elimination of redundant phrases. We have also enhanced the logical flow between sections to ensure a more coherent and precise presentation of the content. To further improve readability, we carefully reviewed subject-verb agreement, article usage, and overall phrasing.   Regarding the concern that the manuscript reiterates established knowledge, we have substantially expanded our discussion to include unresolved challenges, emerging trends, and key research gaps in nanoparticle-based therapeutics for periodontitis. These additions ensure that our review does not simply summarize prior findings but provides a more critical synthesis that contributes meaningful insights to the field. We have also incorporated new references and a stronger evidence-based discussion to highlight potential directions for future investigations.   We greatly value your critical assessment, which has guided us in making substantial improvements to the manuscript. We hope that these revisions successfully address your concerns and significantly enhance the manuscript’s overall quality and impact.   Best regards, A. Mlachkova, V. Dosseva-Panova, H. Maynalovska, Z. Pashova-Tasseva Medical University of Sofia, Faculty of Dental Medicine, Department of Periodontology

 

 

 

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

Thank for providing an improved version of the manuscript

The article improved significantly 

Limited Critical Assessment of the Evidence: The review primarily presents information without a deep critical discussion on the limitations, challenges, and contradictions in the current research. A stronger critique of existing studies, as well as a discussion on future research directions, would enhance its value.

Clinical Relevance is Not Fully Explored: Although the review discusses various nanoparticle-based strategies, it does not provide a clear pathway for clinical translation. The manuscript would benefit from a dedicated section addressing real-world applicability, regulatory challenges, safety concerns, and cost-effectiveness of these therapies.

kind regards

Author Response

Dear Reviewer,   Thank you very much for your valuable and thoughtful feedback. We truly appreciate the time and effort you have dedicated to reviewing our article. In response to your comments, we have incorporated the new information in red font for your convenience.

Comments 1: The article improved significantly   Limited Critical Assessment of the Evidence: The review primarily presents information without a deep critical discussion on the limitations, challenges, and contradictions in the current research. A stronger critique of existing studies, as well as a discussion on future research directions, would enhance its value.   Clinical Relevance is Not Fully Explored: Although the review discusses various nanoparticle-based strategies, it does not provide a clear pathway for clinical translation. The manuscript would benefit from a dedicated section addressing real-world applicability, regulatory challenges, safety concerns, and cost-effectiveness of these therapies.

Response 1: Agree. I/We have, accordingly, revised and modified the discussion and conclusion section to emphasize this point. We have expanded the discussion to include a more in-depth critical assessment of the limitations, challenges, and contradictions in the current research. Additionally, we have outlined potential directions for future research to offer a more comprehensive perspective on the existing evidence. We have added a dedicated section to better address the clinical translation of nanoparticle-based strategies. This new section discusses the real-world applicability, regulatory challenges, safety concerns, and cost-effectiveness of these therapies, providing a clearer pathway for their implementation in clinical settings. The provided changes can be found in both the Discussion and Conclusion sections of the manuscript. The changes can be found on page13, paragraph 2; page 14, paragraphs 1 and 2, lines 503-537; page 15-17, lines 552-660; pages 17-18, lines 681-689.

Dear Reviewer,   Thank you very much for your valuable and thoughtful feedback. We truly appreciate the time and effort you have dedicated to reviewing our article. In response to your comments, we have incorporated the new information in red font for your convenience.  v

Comments 1: The article improved significantly   Limited Critical Assessment of the Evidence: The review primarily presents information without a deep critical discussion on the limitations, challenges, and contradictions in the current research. A stronger critique of existing studies, as well as a discussion on future research directions, would enhance its value.   Clinical Relevance is Not Fully Explored: Although the review discusses various nanoparticle-based strategies, it does not provide a clear pathway for clinical translation. The manuscript would benefit from a dedicated section addressing real-world applicability, regulatory challenges, safety concerns, and cost-effectiveness of these therapies.

Response 1: Agree. I/We have, accordingly, revised and modified the discussion and conclusion section to emphasize this point. We have expanded the discussion to include a more in-depth critical assessment of the limitations, challenges, and contradictions in the current research. Additionally, we have outlined potential directions for future research to offer a more comprehensive perspective on the existing evidence. We have added a dedicated section to better address the clinical translation of nanoparticle-based strategies. This new section discusses the real-world applicability, regulatory challenges, safety concerns, and cost-effectiveness of these therapies, providing a clearer pathway for their implementation in clinical settings. The provided changes can be found in both the Discussion and Conclusion sections of the manuscript. The changes can be found on page13, paragraph 2; page 14, paragraphs 1 and 2, lines 503-537; page 15-17, lines 552-660; pages 17-18, lines 681-689.

We believe these revisions significantly enhance the manuscript and align with your suggestions for improving the critical depth and clinical relevance of the review.   Thank you again for your valuable input.

Round 3

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Author 

Thanks for providing this revised version