Dear Dr. Peng,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Kind regards,

Anisha DSouza, Ph.D (Tech)

Academic Editor

PLOS ONE

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Additional Editor Comments:

Thank you for your patience and for considering our journal for your interesting manuscript. We have now received the reviewers’ comments, which are included below. Based on their feedback, we kindly request that you revise the manuscript by addressing these points carefully. Please do not hesitate to reach out if you have any questions or need clarification.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Line 117

The medium name is written as "DEME". Should this be "DMEM"?

Line 128

It might be helpful to include a description of the quantification method used for the isolated exosomes.

Line 171

The product name appears to be outdated. Should this be updated to "ECL Prime"? If the name differs depending on the sales region, forget about it.

Line 247

Just to confirm: Is my understanding correct that miR-488-3p was only effective when loaded into exosomes?

Line 291

For consistency, would it be possible to label the images in Figure 4B and 4E with "Control", "Exo-NC", and "Exo-miR-488-3p", similar to Figure 5?

Reviewer #2: 1. Line 107 and 109- Please can the authors capitalize the whole primer sequence and maintain consistency throughout the manuscript.

2. Line 80- Mention the full form of DMEM and then abbreviate in the manuscript

3. Line 117- DEME is mentioned instead of DMEM

4. Figure 4- Please can the authors label the diagrams B and E with study groups

5. Please can authors provide an explanation why miR-448-3p activity and effectiveness was not looked at throughout the study?

6. Please can the authors mention how many times the experiments were performed in the figure legend or results

7. Figure 1- Is it possible for the western blot to be repeated, the miR-375-3p has two bands, please can you provide an explanation.

8. Figure 4 A- cell viability just has two lines for 3 groups, can you change it to color or make the third group prominent.

9. Figure 4C- there is no conclusive evidence that the apoptosis numbers were elevated since there is no statistical significance, the authors can confirm this by performing western blot for apoptotic markers like Bax, BCl2, PARP

10. Figure 5- scale bars are missing in the image. Also, some graphs are bordered and some are not, please try to maintain consistency throughout the figures.

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what does this mean? ). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step.

Dear Dr. Peng,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Feb 05 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

• A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Anisha DSouza, Ph.D (Tech)

Academic Editor

PLOS One

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

Thank you for addressing the comments. One reviewer has provided a very minor typographical suggestion. Please address it and share the revised manuscript for the next steps. Thank you.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

Reviewer #1: line 175

Please ensure that the trademark symbol in “ECL-plus™ kit” is formatted as a superscript (™) according to standard typographic conventions. This is a minor formatting issue but should be corrected for consistency.

Reviewer #2: (No Response)

**********

what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #1: No

Reviewer #2: Yes: Advait Shetty

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation.

NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

MicroRNA-488-3p-loaded engineered exosomes inhibit proliferation, migration and invasion of hepatocellular carcinoma by targeting SEC61G

PONE-D-25-40839R2

Dear Dr. Peng,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Anisha DSouza, Ph.D (Tech)

Academic Editor

PLOS One

Additional Editor Comments (optional):

Thank you for addressing the typographical errors.

Reviewers' comments: