Biomolecular Interfaces in Targeted Nano-Drug Delivery: Molecular Recognition, Signaling Modulation, and Translational Pathways

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

biomolecules-4286239

The manuscript entitled “Biomolecular Interfaces in Targeted Nano-Drug Delivery: Molecular Recognition, Signaling Modulation, and Translational Pathways” addresses an important and highly relevant topic in the field of nanomedicine, particularly focusing on biomolecular interactions at the bio–nano interface and their implications for targeted drug delivery. The scope is broad and potentially impactful; however, the manuscript in its current form lacks sufficient depth, structure, and critical analysis to meet the standards of a comprehensive review. The details are as follows.

1. The Introduction requires further development to clearly articulate the motivation for this review, its novelty, and its specific contribution relative to the existing literature. Given the large number of reviews already published on targeted nano-drug delivery systems, it is essential for the authors to explicitly define how this work differs and what unique perspective it offers. At present, this positioning is not sufficiently clear.
2. Several core sections of the manuscript are underdeveloped and lack detailed discussion supported by representative examples. Section 2, which should form the foundation for understanding molecular recognition and design principles, is relatively superficial. The authors should expand this section by incorporating concrete examples that illustrate how targeted nano-drug delivery systems are rationally designed, including their in vitro and in vivo performance.
3. Similarly, Section 3 overlaps conceptually with Section 2 and does not clearly establish the structure–function–biointeraction relationships indicated in its heading. This section would benefit from a clearer organization and more detailed discussion and specific case studies from the literature, particularly with respect to lipid-based and polymeric nanoparticles.
4. The presentation of data can also be significantly improved. Table 1 should be revised to present each study in a structured format, with key details such as nanoparticle type, targeting strategy, biological model, and outcomes. In addition, the inclusion of summary tables for Sections 3.2 and 3.3 would greatly enhance clarity and allow for better comparison across different systems and approaches.
5. Section 4, which addresses applications and translational considerations, is too general and lacks depth. The discussion is largely limited to oncology and inflammatory or autoimmune diseases, without clear justification for this focus or exploration of other relevant therapeutic areas. Moreover, the translational aspects mentioned in the section heading are not sufficiently developed. A more detailed and critical discussion of clinical translation, including regulatory challenges, scalability, safety, and available clinical trial data, is necessary to strengthen the impact of the review.
6. Section 6, covering challenges, opportunities, and future perspectives, is also insufficiently developed (only 20 lines). Given the importance of this section in guiding future research, a more comprehensive and insightful discussion is expected. The current content is brief and does not adequately capture the complexity of the field or provide meaningful forward-looking perspectives.
7. There are also issues related to manuscript organization and presentation. Some subsection numbering appears inconsistent or incomplete (e.g., missing sections such as 3.1.1 or 3.2.2), which should be corrected.
8. All figures should be carefully reviewed to ensure originality and consistency in style and formatting.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript addresses a highly relevant and timely topic in nanomedicine, focusing on biomolecular interfaces and targeted nano-drug delivery systems. The authors cover a wide range of concepts, from targeting mechanisms to material design and translational challenges. The structure is clear and supported by recent literature.

Overall, the manuscript is informative and well organized. However, it remains largely descriptive and would benefit from stronger critical analysis and clearer conceptual synthesis.

1. More description than critical analysis

The manuscript provides numerous examples, but often without sufficient critical evaluation.

• The EPR effect is explained clearly, but its clinical limitations are not fully explored
• Active targeting is described as highly effective, with limited discussion of instability and in vivo challenges

A more balanced discussion of strengths vs limitations would significantly improve the manuscript.

2. Lack of a clear “big picture”

While multiple nanocarrier systems are discussed, the manuscript does not clearly extract general design principles.

The addition of:

• comparative tables
• conceptual summaries
• clear design guidelines

would greatly improve readability and impact.

Suggested improvement:

• Add summary tables or schematic overviews
• Include short take-home messages at the end of sections
• Emphasize general design principles (e.g., size, surface chemistry, responsiveness)

3. Some redundancy throughout the text

Certain ideas are repeated multiple times, such as:

• “enhanced targeting”
• “reduced toxicity”
• “controlled release”

While these are central concepts, their repetition makes the manuscript feel less concise.

• Reduce repetition and focus on synthesis rather than reiteration

4. Figures are clear but too general

The figures (Figures 1–5, particularly those illustrating EPR and active targeting on pages 2–6 ) are visually clear and helpful for basic understanding. However:

• They are largely schematic and resemble educational illustrations
• They do not provide deeper mechanistic insight or comparative analysis

There are missing:

• Comparative visualization of different targeting strategies
• A unifying conceptual figure that connects materials, mechanisms, and applications

My concrete suggestion:

• Include at least one integrative “framework” figure summarizing the relationships between nanocarrier design, targeting mechanisms, and clinical translation

4a. Figures: scientific value and transparency

The figures (Figures 1–5, pages 2–6 ) are clear and support the text, but they are largely schematic and do not provide deeper analytical or comparative insight.

In addition, the origin of the figures is not specified, which is an important issue.

It is unclear whether the figures are:

• original
• adapted from previous publications
• or generated using standard graphical tools

This lack of clarity raises concerns related to:

• attribution
• originality
• and potential copyright compliance

The authors should explicitly state the source of each figure. If any figures are adapted or reproduced, appropriate references and permissions must be provided. Furthermore, the manuscript would benefit from more integrative figures (e.g., conceptual frameworks or comparative schematics).

Figure originality and potential reuse concerns

Related to the point above, several figures appear highly standardized and resemble commonly used schematic representations of nano-drug delivery mechanisms.

While this does not necessarily indicate inappropriate reuse, the current presentation makes it difficult to assess whether:

• the figures are fully original
• partially adapted
• or conceptually reproduced from prior literature

Greater transparency is needed.

The authors should clearly indicate whether the figures are original or adapted and ensure that all visual elements comply with journal policies regarding image reuse and copyright. If created using graphical platforms (e.g., BioRender), this should also be stated in the figure captions.

This clarification is important not only for compliance but also for maintaining scientific transparency.

5. The AI section is underdeveloped

Artificial intelligence is mentioned briefly, but the discussion remains quite superficial.

Given the growing importance of AI in nanomedicine:

• this section feels incomplete

Some suggested improvement:

• Include concrete examples (e.g., machine learning in nanocarrier design, ligand optimization)
• Expand the discussion on future perspectives

Minor comments

• Some sentences are quite long and could be simplified for clarity
• Abbreviations should be consistently defined at first mention
• Figure legends could be more detailed and self-explanatory
• The balance between sections could be improved (some are much more detailed than others).

This is a well-structured and relevant review with strong potential. To meet the expectations of a high-quality review article, the manuscript would benefit from:

• stronger critical analysis
• clearer conceptual synthesis
• reduced redundancy
• more informative and integrative figures
• a more developed discussion on emerging topics such as AI

 

Comments on the Quality of English Language

The manuscript is generally well written. However, minor language polishing would further improve readability and flow, particularly by simplifying longer sentences and reducing repetition.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Thanks for providing the revised manuscript and the response letter. Below are some issues to consider.

1. Figures: Please confirm that there is no copyright issue with the Figures. Please revise them to keep their style (such as text font and size) consistent among the Figures.
2. There is only section 3.2.1 but no section 3.2.2.

Author Response

Dear Reviewer 1,

Thank you very much for your highly constructive comments and careful evaluation of our manuscript. We have carefully considered your suggestions and revised the manuscript accordingly. Below is a point-by-point response to your comments.

Comment 1: Figures: Please confirm that there is no copyright issue with the Figures. Please revise them to keep their style (such as text font and size) consistent among the Figures.

Response 1: Thank you for highlighting this important point. We confirm that there are no copyright issues with the figures presented in this manuscript. Specifically: Figure 1 is original and was created by our team using Adobe Illustrator. Figures 2 and 3 were adapted from Biorender.com and created using Adobe Illustrator. We hold the appropriate usage rights for these Biorender assets. Figures 4 and 5 were adapted from references [36] and [65], respectively, and re-drawn using Adobe Illustrator. We have ensured that all adaptations comply with necessary copyright and attribution guidelines, and the corresponding sources are clearly stated in the figure legends.

We have carefully revised and re-exported all figures to ensure a uniform visual style. The text font, font size, line weights, and overall visual formatting have been strictly standardized across all figures (Figures 1 to 5) to improve readability and maintain aesthetic consistency throughout the manuscript.

Comment 2: There is only section 3.2.1 but no section 3.2.2.

Response 2: We apologize for this structural oversight in the previous version of the manuscript. In response to your comment, we have thoroughly updated the section formatting to ensure a logical structural flow. Under Section 3.2 (Polymer nanoparticles), the manuscript now correctly pairs "3.2.1. Synthetic Biodegradable Polymers: PLGA-Based Delivery Systems" with the newly structured "3.2.2. Natural Polysaccharides: Chitosan and Guar Gum-Based Systems".

Reviewer 2 Report

Comments and Suggestions for Authors

The revised version of the manuscript has improved substantially compared with the original submission. The authors addressed most of the major concerns raised during the previous review round, particularly by improving the critical discussion, reducing redundancy, adding comparative tables, and expanding the AI-related section. The manuscript is now clearer, better structured.

However, several issues should still be addressed:

1. Although the manuscript is now more balanced and analytical, some sections still rely heavily on sequential presentation of examples from the literature. In particular, Sections 3 and 4 would benefit from a clearer synthesis of the major design principles emerging across studies, such as the relationship between particle size, surface chemistry, targeting strategy, responsiveness, biological barriers, and translational applicability. At present, many examples are presented individually, but the broader comparative conclusions are not always sufficiently emphasized.
2. The addition of Tables 1–4 significantly improves readability and organization. However, the tables should be carefully revised for formatting consistency, including spacing, symbols, line breaks, and overall readability.
3. The figures are clear and useful, but many remain highly schematic and resemble standard educational illustrations. Greater transparency regarding figure preparation is still needed. The figure captions should explicitly state: whether the figures are fully original or partially adapted; and which software/platform was used for figure generation (e.g., BioRender or similar tools, if applicable).
4. The manuscript would benefit from at least one more integrative conceptual figure linking: nanocarrier materials,targeting mechanisms,biological barriers, and translational applications/challenges.

This would strengthen the overall conceptual synthesis of the manuscript.

1. Please carefully verify the resolution and quality of all figures before final submission. Some figures appear slightly compressed, and all labels and annotations should remain fully readable in publication format.
2. A final careful revision of the bibliography and formatting is recommended to ensure consistency in references, abbreviations, citation style, and typography throughout the manuscript.
3. The AI-related section is improved and more relevant in the revised version. However, a brief acknowledgment of current limitations of AI-driven approaches in nanomedicine would further strengthen the discussion.
4. The manuscript is generally well written, but several long sentences and repetitive formulations remain. A final round of language polishing would improve readability and flow.

 

Author Response

Dear Reviewer 2,

Thank you very much for your insightful comments and constructive feedback. Your suggestions have been instrumental in helping us refine the manuscript, particularly regarding the conceptual synthesis and figure transparency. We have carefully addressed each of your concerns as detailed below.

Comment 1: Although the manuscript is now more balanced and analytical, some sections still rely heavily on sequential presentation of examples from the literature. In particular, Sections 3 and 4 would benefit from a clearer synthesis of the major design principles emerging across studies, such as the relationship between particle size, surface chemistry, targeting strategy, responsiveness, biological barriers, and translational applicability. At present, many examples are presented individually, but the broader comparative conclusions are not always sufficiently emphasized.

Response 1: We strongly agree with your assessment. To move beyond a sequential presentation and provide a stronger conceptual synthesis, we have added a dedicated new section, "3.5. Comparative Synthesis of Nanocarrier Design Principles". This section explicitly compares the intrinsic properties (size, surface chemistry) of lipid, polymeric, inorganic, and biological carriers and links them to their targeting capabilities and translational barriers. Furthermore, in Section 4.2, we have added a comparative paragraph summarizing the distinct structure-function-barrier relationships when comparing oncology with inflammatory disease models.

Comment 2: The addition of Tables 1–4 significantly improves readability and organization. However, the tables should be carefully revised for formatting consistency, including spacing, symbols, line breaks, and overall readability.

Response 2: Thank you for this meticulous observation. We have conducted a thorough review and formatting adjustment of Tables 1–4. We have standardized the line spacing, alignment, symbols (e.g., ensuring consistent use of statistical markers and Greek letters), and line breaks to ensure a clean, professional, and consistent appearance across all tables.

Comment 3: The figures are clear and useful, but many remain highly schematic and resemble standard educational illustrations. Greater transparency regarding figure preparation is still needed. The figure captions should explicitly state: whether the figures are fully original or partially adapted; and which software/platform was used for figure generation (e.g., BioRender or similar tools, if applicable).

Response 3: We apologize for the lack of transparency in the previous draft. Following your instructions, we have updated the captions for all figures (Figures 1–5) to explicitly detail their origin and the software used for their creation. For instance, we now clearly denote which figures are fully original (created with Adobe Illustrator), which incorporate elements adapted from BioRender.com, and which are redrawn based on specific literature citations.

Comment 4: The manuscript would benefit from at least one more integrative conceptual figure linking: nanocarrier materials, targeting mechanisms, biological barriers, and translational applications/challenges.

Response 4: We deeply appreciate this suggestion. We spent considerable time exploring the design of such an all-encompassing integrative figure. However, we found that attempting to compress four complex dimensions (materials, mechanisms, barriers, and challenges) into a single graphic resulted in an overly dense and visually overwhelming illustration, which compromised the clarity you rightly expect. To achieve the exact conceptual synthesis you recommended without sacrificing readability, we opted to strengthen the textual integration instead. Specifically, the newly added Section 3.5 and the comparative summaries in Section 4 explicitly connect these four parameters. We believe this textual synthesis, combined with the structured comparisons in Tables 1–4, effectively accomplishes the goal of linking these concepts in a clear and rigorous manner. We hope you will find this approach satisfactory.

Comment 6: Please carefully verify the resolution and quality of all figures before final submission. Some figures appear slightly compressed, and all labels and annotations should remain fully readable in publication format.

Response 6: We have carefully re-examined all figures. The original files have been re-exported at a high resolution to eliminate any compression artifacts. We have also verified that all labels, text, and annotations remain sharp and fully readable at standard publication dimensions.

Comment 7: A final careful revision of the bibliography and formatting is recommended to ensure consistency in references, abbreviations, citation style, and typography throughout the manuscript.

Response 7: We have conducted a rigorous final proofreading of the entire manuscript. We verified the consistency of all abbreviations upon their first use, standardized the typography, and rigorously checked the bibliography to ensure strict adherence to the journal's citation formatting guidelines.

Comment 8: The AI-related section is improved and more relevant in the revised version. However, a brief acknowledgment of current limitations of AI-driven approaches in nanomedicine would further strengthen the discussion.

Response 8: This is a very sharp and valuable insight. We completely agree that a balanced view must include current limitations. We have expanded Section 5.3 to acknowledge these hurdles explicitly. The manuscript now discusses the heavy reliance on high-quality, standardized in vivo datasets, which remain highly fragmented, as well as the inherent "black box" nature of complex predictive models that complicates regulatory assessment.

Comment 9: The manuscript is generally well written, but several long sentences and repetitive formulations remain. A final round of language polishing would improve readability and flow.

Response 9: We appreciate your positive overall feedback on the writing. Following your advice, the entire manuscript has undergone a final round of careful language editing. We have restructured overly long sentences for better clarity, removed repetitive phrasing, and refined the transitions between paragraphs to ensure a smoother narrative flow.