Biofunctional Peptide-Modified Extracellular Vesicles Enable Effective Intracellular Delivery via the Induction of Macropinocytosis
Round 1
Reviewer 1 Report
This review submitted for publication by Prof. Nakase describes the role of macropinocytosis in the cellular uptake of exosomes and the methods for modification of biofunctional peptides on exosomes to induce macropinocytosis in targeted recipient cells. This is an interesting topic for the field, appropriate for Processes, but that should be amplified considering that the author is submitting a paper as review type.
In that form, it is too short to be considered as review and it is mainly focused on the work made by the author which led to observe too many self-citations. Thus, the paper is not accetable as it is. It can be considered again after a deep investigation of literature data which surely contribute to enlarge the discussion and the description of the recent developed approaches in this research field.
More examples, as expected by a review, of arginine-rich peptides and of the other chemical compounds involved into pinocytosis should be added. Only, by this extensive reorganisation of the paper, it could be further considered.
Author Response
I would like to thank Referee #1 for the constructive comments and suggestions for improving our manuscript. A point-by-point response to these comments/suggestions is given below.
Reviewer: 1
This review submitted for publication by Prof. Nakasedescribes the role of macropinocytosis in the cellularuptake of exosomes and the methods for modification ofbiofunctional peptides on exosomes to inducemacropinocytosis in targeted recipient cells. This is aninteresting topic for the field, appropriate for Processes, butthat should be amplified considering that the author issubmitting a paper as review type.
Response to remark: I sincerely appreciate the reviewer’s positive comments.
Comments:
In that form, it is too short to be considered as review and itis mainly focused on the work made by the author whichled to observe too many self-citations. Thus, the paper isnot accetable as it is. It can be considered again after adeep investigation of literature data which surely contributeto enlarge the discussion and the description of the recent developed approaches in this research field.More examples, as expected by a review, of arginine-richpeptides and of the other chemical compounds involvedinto pinocytosis should be added. Only, by this extensivereorganisation of the paper, it could be further considered.
Response to remark: I would like to express our gratitude for the reviewer’s suggestion.As followed as the reviewer’s comments, I added “active target systems based on exosomes recently developed” as new section 5 especially including new important findings and techniques, which contribute to development for therapeutic applications. Concerning micropinocytosis induction, mechanisms of macropinocytosis have been elucidated in detail, however, there are few macropinocytosis inducers reported including arginine-rich peptides, and ligands for macropinocytosis inducible cancer-related receptors such as EGFR and CXCR4, therefore, further development of macropinocytosis inducer, which is useful for enhancing cellular uptake in not only exosome-based intracellular delivery but also other system such as antibody-based delivery (Nakase et al. ACS Omega(2020)) and liposomes should be needed. The points were also added in the revised manuscript. Again, I sincerely appreciate the reviewer’s important suggestion.
Author Response File: 
Author Response.docx
Reviewer 2 Report
The article focuses on the results, achieved by the author's scientific group on the topic of exosomal delivery systems that is from one point sums up the results of the group, but from other, lacking comparison to the progress made by other scientific groups in the field. In order to improve the potential impact of the article several points are advised:
- It would be nice to describe other approaches for the targeted delivery of exosomes in section 4.
- Section 4 and 5: numbers are missing, when the several-fold increase in uptakes and efficiencies are postulated related to non-modified systems it is unclear how this increase impacts the overall low cellular uptake efficacy of exosomes. Does it make them comparable to other delivery systems such as liposomes for instance? In section 5 the results are described as "significantly increased" without any numerical explanations.
Author Response
I would like to thank Referee #2 for the constructive comments and suggestions for improving our manuscript. A point-by-point response to these comments/suggestions is given below.
Reviewer: 2
The article focuses on the results, achieved by the author'sscientific group on the topic of exosomal delivery systemsthat is from one point sums up the results of the group, butfrom other, lacking comparison to the progress made byother scientific groups in the field. In order to improve thepotential impact of the article several points are advised:
- It would be nice to describe other approaches for the targeted delivery of exosomes in section 4.
Response to remark: I would like to express our gratitude for the reviewer’s suggestion.As followed as the reviewer’s comments, I added “active target systems based on exosomes recently developed” as new section 5 especially including new important findings and techniques, which contribute to development for therapeutic applications.
- Section 4 and 5: numbers are missing, when the several-fold increase in uptakes and efficiencies are postulated related to non-modified systems it is unclear how this increase impacts the overall low cellular uptake efficacy of exosomes. Does it make them comparable to other delivery systems such as liposomes for instance? In section 5 the results are described as "significantly increased" without any numerical explanations.
Response to remark: I am grateful for the reviewer’s important comments. As followed as the reviewer’s comments, I added the important information for easily understanding each enhanced cellular uptake efficacy in the revised manuscript.
Author Response File: Author Response.docx
Round 2
Reviewer 1 Report
The author provided a revised version of its manuscript addressing all suggestions and comments raised by the previous peer-review process. The manuscript has been improved and its content has been enlarged covering new and interesting topic.
I have no further comments, so the review can be accepted for publication in this form.
