Dear Dr. falawish,

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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We look forward to receiving your revised manuscript.

Kind regards,

Hualin Wang

Academic Editor

PLOS ONE

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 [This work was funded by the Deanship of Scientific Research in cooperation with Olive Research Center at Jouf University under Grant Number (DSR2022-RG-0164).]. 

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Additional Editor Comments (if provided):

[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: Partly

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

Reviewer #1: Yes

Reviewer #2: No

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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

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

Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: This manuscript is " Exosomes combined with extra virgin olive oil reduces lipogenesis, oxidative stress, and inflammation in non-alcoholic fatty liver disease model ". The topic of this manuscript is interesting and suitable for publication in the journal. However, some points need explanation, which are mentioned below:

1. Do not use abbreviations in the keywords section.

2. In the introduction, you explained that extra virgin oil has important nutritional effects. Given that impurities in the oil are not removed, please also explain if it has anti-nutritional properties.

3. Could the special properties of extra virgin oil be due to compounds other than fatty acids and total antioxidant?

4. Did you determine the composition of extra virgin oil؟

5. It is not necessary to use "showing" at the beginning of the names of arguments and forms.

Reviewer #2: This study used exosomes derived from BM-MSCs, combined with extra virgin olive oil (EVOO), to treat high fat diet fed rat. The authors reported that administration of olive oil, or exosomes, significantly improved hyperlipidemia in rats, including rat’s body weight, plasma lipid parameters, liver parameters, and lipogenesis-related gene expression; however, the combined EVOO+Exo group had the best improvements. This study is the first to combine exosomes with olive oil for the treatment of NAFLD.

Major issues:

1. Statistical analysis: in the figure legend, “Bars with different letters show statistical significance between groups (P<0.05) using Tukey's HSD.” What do different letters exactly mean? a, b, c? Please provide all the p values.

2. Related to issue 1. From the bar charts shown in certain figures, the efficacy advantage of combined administration seems to be not significant when compared with olive oil or exosomes.

3. In the experimental design, the hyperlipidemia group was treated with 50μg of exosomes derived from BM-MSCs once a week by intraperitoneal injection. Why did the author use i.p., instead of i.v.? In addition, how to determine the dosage of exosomes?

4. The phenotype of NAFLD in the rat model is not obvious. Is there any index of NAFLD in rats fed with high fat diet? Or is the disease model just hyperlipidemia?

Minor issues:

1. Figure 4: label arrow, arrowhead correctly.

2. Make sure the references are appropriate.

3. Some sentences are repetitive, such as page 15, line 8-10.

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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.

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Reviewer #1: No

Reviewer #2: Yes:  chen wang

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[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.

Attachments

Attachment

Submitted filename: Comments.docx

Dear Dr. Falawish,

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 Aug 16 2025 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 rebuttal 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 you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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,

Hualin Wang

Academic Editor

PLOS ONE

Additional Editor Comments:

The authors should explain the dosage of exosomes and the statistical analysis carefully.

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: (No Response)

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

Reviewer #2: Yes

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

Reviewer #2: I Don't Know

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

The PLOS Data policy

Reviewer #2: Yes

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

Reviewer #2: Yes

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Reviewer #2: Related to comment 3:

About the injection method and dosage of exosomes, please add references to support this and discuss.

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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 #2: No

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[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.

Exosomes combined with extra virgin olive oil reduces lipogenesis, oxidative stress, and inflammation in non-alcoholic fatty liver disease model

PONE-D-25-10509R2

Dear Dr. falawish,

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.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Hualin Wang

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Please check page 57, as the reviewer 2 mentioned: "When explaining exosome dosage and administration, there are some repetitive statements. Please revise.".

Reviewer #2:

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

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

Reviewer #2: Yes

**********

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

Reviewer #2: Yes

**********

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

The PLOS Data policy

Reviewer #2: Yes

**********

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

Reviewer #2: Yes

**********

Reviewer #2: Page 57: When explaining exosome dosage and administration, there are some repetitive statements. Please revise.

**********

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 #2: No

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