A Proposed Microneedle–Small Extracellular Vesicle System for Localized Adjunctive Treatment of Established Oral Squamous Cell Carcinoma: A Narrative Review and Preclinical Development Perspective

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors,

Thank you for the opportunity to review this paper. Your manuscript addresses an important and emerging topic. It is scientifically informed and clinically relevant, covering a large amount of literature. You have recognized the limited direct evidence supporting microneedle-sEV systems in OSCC.

Yet, I have some suggestions for improvement:

-please shorten the manuscript. It is excessively long and it is hard to follow this amount of text.

- you have mentioned Level 1–5 evidence hierarchy; please cite reference or explain whose classification it is

-the table on page 21 is missing a title

-try using bullets in the tables to reduce the amount of text

-there are some minor English language mistakes (for example, "invsive", "mehanical")

 

Comments on the Quality of English Language

There are some minor English language mistakes (for example, "invsive", "mehanical"); please review the English language in the paper.

Author Response

Please see the attachment

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

Major comments:

1. Can the authors argue the value of publishing this review beyond a highly speculative idea? The manuscript is mainly a proposal for the future, as direct evidence for OSCC using the microneedle-sEV platform is very limited.
2. Can the authors better distinguish between evidence and speculation throughout the manuscript? Many of the claims are presented too forcefully, given that they are mostly based on indirect evidence.
3. Could the authors limit the scope and sharpen the conceptual focus? The review is too broad in the application domains; therefore, the main argument is weakened.
4. Could the authors provide stronger mechanistic evidence related to OSCC before making translational claims? Many of the supports are from non-OSCC models, which are not fully transferable to OSCC.
5. Perhaps authors will be more careful about safety and product consistency issues? Key issues remain unresolved, including sEV heterogeneity, pro-tumor risk, quality control, and long-term safety.
6. Authors may simplify the schematic diagram and make it more representative of the current level of evidence. The figure is cluttered and combines validated and indirect and hypothetical concepts without clear distinction. 

Minor comments:

1. Can the authors not be more careful in their terminology? Inconsistent use of “sEVs”, “exosomes” and “extracellular vesicles”.
2. Authors may downplay unnecessary discussion of gaps in evidence. The same limitation is repeated too many times.
3. Would the authors have made some of the dense paragraphs and tables easier to read? Such structure would be more concise and hence would make the manuscript more readable.

Comments on the Quality of English Language

Could the authors moderate the use of language describing the platform advantages? Some of the language is stronger than can be supported by the evidence.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript by He and Chen et al., presents an interesting and potentially useful concept by integrating microneedle technology with small extracellular vesicles (sEVs) for localized oral squamous cell carcinoma (OSCC) therapy.

I have a few comments for polishing the manuscript.

1. The manuscript repeatedly acknowledges that direct evidence for microneedle–sEV systems in OSCC is scarce. Consequently, the title and several statements may overstate the translational maturity of this approach. The authors should consistently describe the system as a proposed or conceptual platform rather than an established therapeutic strategy.
2. The manuscript is excessively long and repetitive. Similar discussions concerning limited direct evidence, sEV heterogeneity, standardization, safety, and translational barriers appear in several sections. Substantial condensation of the manuscript is recommended.
3. The authors should strengthen the manuscript by discussing salivary non-coding RNAs as potential molecular cargo of sEVs for OSCC diagnosis and prognosis. Since sEVs can transport and protect miRNAs, circRNAs, and lncRNAs in saliva, these molecules may provide a biological basis for the proposed microneedle-assisted collection of lesion-proximal vesicles and integrated theranostic applications. The authors should review the following articles in this regard

https://doi.org/10.3390/ncrna11020028

https://doi.org/10.1016/j.clinthera.2015.02.017

4. Several citations appear insufficiently aligned with the claims they support. The authors should conduct a complete reference audit, prioritizing original studies over secondary reviews.
5. Use “sEV,” “sEVs,” and “microneedle–sEV system” consistently.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

In the revised article, the authors comprehensively addressed the reviewer's comments by modifying the manuscript and figures and thoroughly answering all questions.

Author Response

Dear Reviewer,

Thank you very much for your positive response and for your recognition of our revisions. We sincerely appreciate the time and effort you devoted to reviewing our manuscript and providing valuable comments throughout the review process.

Your constructive suggestions have greatly helped us improve the quality and clarity of the manuscript. We are very grateful for your thoughtful evaluation and kind feedback.

Sincerely,
The Authors

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript can be accepted in its present form.

Author Response

Dear Reviewer,

Thank you very much for your positive response and for your recognition of our revisions. We sincerely appreciate the time and effort you devoted to reviewing our manuscript and providing valuable comments throughout the review process.

Your constructive suggestions have greatly helped us improve the quality and clarity of the manuscript. We are very grateful for your thoughtful evaluation and kind feedback.

Sincerely,
The Authors