Nanocarrier-Based Therapeutic Strategies in Myocardial Ischemia–Reperfusion Injury: A Systematic Review of Preclinical Evidence
, Bartosz Pawełczak 2,*, Karolina Barańska-Pawełczak 3,* and Krzysztof Marciniec 4
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis paper summarizes the recent progress of nanotherapy for myocardial ischemia-reperfusion injury ($MIRI$). The topic is very popular in recent years, but I have several big concerns about the methodology and the depth of the discussion.
First, I have a big concern about the literature search. The authors only included 8 studies in the final review. This number is very small for a "systematic review." The authors only searched the PubMed database and limited the time from 2023 to 2025. I worry that many important papers from other databases (like Embase or Web of Science) are missed. The authors must justify why they chose such a narrow window and only one database. Without more papers, the generalizability of the conclusions is weak.
Secondly, the discussion of the 8 studies is not deep enough. Most studies show similar results, like improved $LVEF$ or reduced infarct size. Because the paper only has 8 studies, the authors should provide more detailed head-to-head comparisons. For example, the authors mention PLGA-based particles , niosomes , and silica nanoparticles. Which nanocarrier is more efficient for heart targeting? It would be better to have a table or discussion comparing the targeting efficiency and bio-distribution of these different platforms.
Thirdly, the section about "translational relevance" is too general. The authors talk about GMP production and regulatory issues, but it feels like a template. I suggest the authors discuss the specific materials in the 8 papers. For example, Ma et al. (2025) used diselenide bonds and Sutariya et al. (2024) used aptamers. Are these materials easy to produce in large scale? What are the specific safety risks for these chemical structures? Please provide professional analysis based on these specific studies.
Finally, the figures in this paper do not provide much value for a review. Figure 1 is just a basic chemical structure of PLGA based on another review paper. Figure 2 is the PRISMA diagram, but with only 8 papers, it is not very necessary. Figure 3 (Table 1) lists information but does not have deep comparison or critique. Overall, the review lacks the deep analysis needed for a high-quality journal.
Author Response
Dear Reviewer 1,
I would like to thank you for careful revision of manuscripts entitled “Nanocarrier-based therapeutic strategies in myocardial ischemia–reperfusion injury: a systematic review of preclinical evidence” and relevant remarks that improve the substantive rank of this work. The replies to your comments are presented as changes in paragraphs with the use of red font. Changes in the manuscript are highlighted in yellow.
Comment 1: First, I have a big concern about the literature search. The authors only included 8 studies in the final review. This number is very small for a "systematic review." The authors only searched the PubMed database and limited the time from 2023 to 2025. I worry that many important papers from other databases (like Embase or Web of Science) are missed.
Response 1: We appreciate the reviewer’s important comment regarding the literature search. In response to this concern, we have expanded our search strategy to include additional databases (Embase and Web of Science) and extended the time frame to 2020-2026. This has increased the comprehensiveness of this review.
Comment 2: The authors must justify why they chose such a narrow window and only one database.
Response 2: Thank you for this important comment. The initial search strategy was designed to focus on the most recent advances in nanocarrier-based therapies for myocardial ischemia-reperfusion injury, given the rapidly evolving nature of this field. However, in response to the Reviewer’s concern, we have expanded the literature search to include additional databases (Embase and Web of Science). The revised PRISMA flow diagram are now provided in the Results section.
Comment 3: Secondly, the discussion of the 8 studies is not deep enough.
Response 3: Thank you for this valuable comment. To address this concern, the literature search was expanded to include additional databases (Embase and Web of Science) and the time frame was extended to 2020-2026. As a result, the number of included studies increased from 8 to 24.
Comment 4: Because the paper only has 8 studies, the authors should provide more detailed head-to-head comparisons.
Response 4: Thank you for this important remark. To address this concern, the literature search was expanded to include additional databases (Embase and Web of Science) and the time frame was extended to 2020-2026. As a result, the number of included studies increased from 8 to 24.
Comment 5: For example, the authors mention PLGA-based particles , niosomes , and silica nanoparticles. Which nanocarrier is more efficient for heart targeting?
Response 5: Thank you for this valuable comments. After reviewing the studies included in this review, we have updated the manuscript with this information. The added sentences are located in lines 633-639.
Comment 6: It would be better to have a table or discussion comparing the targeting efficiency and bio-distribution of these different platforms.
Response 6: Thank you for this important remark. In response we have added a dedicated table (table 1) summarizing and comparing targeting strategies and biodistribution profiles across the included nanocarrier platforms.
Comment 7: Thirdly, the section about "translational relevance" is too general.
Response 7: We are grateful for this helpful observation. We agree that the previous version of the manuscript presented the translational relevance in an overly general manner. In response, we have substantially revised the section to include a material-specific analysis of the nanocarriers used in the included studies. The added sentences are located in lines 685-710.
Comment 8: I suggest the authors discuss the specific materials in the 8 papers. For example, Ma et al. (2025) used diselenide bonds and Sutariya et al. (2024) used aptamers. Are these materials easy to produce in large scale? What are the specific safety risks for these chemical structures? Please provide professional analysis based on these specific studies.
Response 8: Thank you for this important remark. In response, we have provided a focused analysis of the specific materials used in included in this review studies. The relevant discussion has been added in lines 676-713.
Comment 9: Finally, the figures in this paper do not provide much value for a review. Figure 1 is just a basic chemical structure of PLGA based on another review paper. Figure 2 is the PRISMA diagram, but with only 8 papers, it is not very necessary. Figure 3 (Table 1) lists information but does not have deep comparison or critique. Overall, the review lacks the deep analysis needed for a high-quality journal.
Response 9: Thank you for this valuable comment. In response, the manuscript has been substantially revised. The literature search was expanded, increasing the number of included studies from 8 to 24. In our opinion, with the expanded dataset, both the PRISMA flow diagram and Figure 1 now provide meaningful context for this review. Additionally, the Discussion section has been expanded to provide deeper comparative analysis of the included studies.
Reviewer 2 Report
Comments and Suggestions for AuthorsIn this study the authors address an important topic about (Nanocarrier-based therapeutic strategies in myocardial ischemia–reperfusion injury: a systematic review of preclinical evidence). Despite this some points should be addressed before publishing.
Title is well written and informative.
Abstract,is well written and adhere standard abstract writing.
Introduction, please add details about MIRI epidemiology risk factors and therapeutic modilities
Moreover add MIRI therapeutic challenges and nanocarriers as promising solutions. As well add details about different nanocarriers. Please add more details about gaseous therapy alongside H2S such as nitric oxide, carbon monoxide, and nanocarriers loaded therapeutic gases as therapeutic modilities for MIRI. At the end of introduction section please add the study rationale and emphasize the study aims.
Methods, please add the inclusion and exclusion criteria.
Results, please include diagram illustrates MIRI therapeutic modilities, mechanisms and nanocarriers types.
Discussion, please discuss the study novelty and limitations.
Conclusions, should be concise and precise.
Please check the manuscript for misuse of acronyms, each acronym should be written at first mentioned,e.g AMI, and others.
Please check the manuscript for the long sentences or paragraphs without references citation.
Comments on the Quality of English Language
Please check the manuscript for minor grammar errors and syntax.
Author Response
Dear Reviewer 2,
I would like to thank you for careful revision of manuscripts entitled “Nanocarrier-based therapeutic strategies in myocardial ischemia–reperfusion injury: a systematic review of preclinical evidence” and relevant remarks that improve the substantive rank of this work. The replies to your comments are presented as changes in paragraphs with the use of red font. Changes in the manuscript are highlighted in yellow.
Comment 1: Introduction, please add details about MIRI epidemiology risk factors and therapeutic modalities
Response 1: Thank you for this suggestion. We have expanded the manuscript by adding information on the epidemiology of MIRI, risk factors and therapeutic strategies. The added sentences are located in lines 44-46, 54-66 and 76-110.
Comment 2: Moreover add MIRI therapeutic challenges and nanocarriers as promising solutions.
Response 2: Thank you for this important remark. The added sentences discussing MIRI therapeutic challenges and nanocarrier-based therapies as promising solutions in MIRI are located in lines 136-157.
Comment 3: As well add details about different nanocarriers.
Response 3: Thank you for this valuable comment. To address this point, the literature search was expanded, increasing the number of included studies from 8 to 24. Consequently, the manuscript now includes additional details regarding different types of nanocarriers discussed in the reviewed studies.
Comment 4: Please add more details about gaseous therapy alongside H2S such as nitric oxide, carbon monoxide, and nanocarriers loaded therapeutic gases as therapeutic modalities for MIRI.
Response 4: Thank you for this insightful comment. We have revised the Introduction section to include additional information on gaseous therapies in MIRI, adding information of NO and CO. The added sentences are located in lines 174-191. Besides that we further expanded the scope of the literature search and included the study by Xu et al. (2024), which describes a nanocarrier-based strategy influencing the NO pathway through L-arginine delivery.
Comment 5: At the end of introduction section please add the study rationale and emphasize the study aims.
Response 5: Thank you for this valuable comment. A study rationale has been added at the end of the Introduction section and the study aim has been strengthened to better clarify the purpose and scope of this review. The fragments have been located in lines 223-227.
Comment 6: Methods, please add the inclusion and exclusion criteria.
Response 6: Thank you for this important remark. We have added inclusion and exclusion criteria in Methods section. The added inclusion and exclusion criteria are located in lines 242-249.
Comment 7: Results, please include diagram illustrates MIRI therapeutic modalities, mechanisms and nanocarriers types.
Response 7: Thank you for this valuable comment. We have added a schematic diagram (Figure 3) in the results section (Section 3.2) illustrating the key pathophysiological mechanisms of MIRI, corresponding therapeutic modalities and nanocarrier platforms.
Comment 8: Discussion, please discuss the study novelty and limitations.
Response 8: Thank you for this suggestion. In response to your suggestion, we have revised and expanded this section. The added sentences can be found in lines 720-723 and 725-726.
Comment 9: Conclusions, should be concise and precise.
Response 9: Thank you for this valuable comment. The Conclusions section has been completely revised and rewritten to ensure greater conciseness and precision. The rewritten conclusion is located in lines 744-751.
Comment 10: Please check the manuscript for misuse of acronyms, each acronym should be written at first mentioned,e.g AMI, and others.
Response 10: Thank you for this important remark. We have carefully reviewed the manuscript and ensured that all acronyms are correctly introduced with their full form upon first mention.
Comment 11: Please check the manuscript for the long sentences or paragraphs without references citation.
Response 11: Thank you for this valuable comment. We have carefully revised the manuscript to ensure that long sentences or paragraphs are appropriately supported by relevant references. The added citations are located in lines 111-125. If the Reviewer identifies any additiona statements that, in their opinion, require further referencing, we would greatly appreciate such guidance.
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsIt looks much better right now, I am pleased to accept it for publication.
