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Review
Peer-Review Record

Therapeutic Innovations for Monkeypox Inhibition

Int. J. Mol. Sci. 2026, 27(10), 4307; https://doi.org/10.3390/ijms27104307
by Nayan De 1,†, Jhuma Bhadra 2,3,†, Md Sorique Aziz Momin 4, Kamala Mitra 5, Debmalya Bhunia 6,* and Achinta Sannigrahi 7,*
Reviewer 1:
Reviewer 2: Anonymous
Reviewer 3: Anonymous
Int. J. Mol. Sci. 2026, 27(10), 4307; https://doi.org/10.3390/ijms27104307
Submission received: 30 March 2026 / Revised: 3 May 2026 / Accepted: 6 May 2026 / Published: 12 May 2026
(This article belongs to the Special Issue Molecular Advances in Zoonoses and Vector-Borne Diseases)

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Conclusion and recommendations are more  than enough

It is very long paper without any need

There is no simple summary or running title

Huge numbers of abbreviations were detected, it is better to create a separate table for this

Abstract :

There are no highlights added after the abstract

There is no graphical abstract

What is/are the creativity of this work/

LN/27-28---Avoid usage of some words, already used with the main topic as keywords

Tabulate all abbreviations

LN/20—CRISPR—detailed then abbreviate—clarify its role also

LN/24—nanocarriers—detailed this /how

Abstract is very short—expand your data

Add some words like backgrounds/aims/methods/conclusion and recommendations

Add nanotechnology/differential diagnosis/molecular pathways/vaccination to the keywords

Introduction

LN/32/40/57/61/88--add references

LN/32—zoonotic infection—describe changes related to both humans and animals /methods of diagnosis

LN/54-55—readjust it

LN/55—surg—what?

MPXV—pathogenesis/molecular pathogenesis /treatment should be enclosed with an updated reference

What about MPXV mutation stressors/mode/avoidance?

Introduction should be more concise

Novelty should be more clarified

Aims should be more highlighted

2

LN/100—endocytosis---how

LN/100—more details are requested/transcription machinery---its role in induction of the disease in chart

LN/105/109—add reference

LN/109—what about MPXV—inclusion bodies and its role in the diagnosis (differential diagnosis)

LN/113-114—molecular pathogenesis is requested

LN/123-124---more details about mechanism/each in chart

3

LN/131/154/156/159/169—add references

Huge numbers of abbreviations were detected, it is better to create a separate table for this

LN.148—2 different styles of writing references were observed---same style should be –apply for all

LN/154—detailed this

LN/169—how would be modified

What about the MPXV pathology

What about the clinical signs/symptoms

What about the PM lesions

Are there any recorded mortalities—what percent

Conclusion

More than enough

3-4 sentences are considered

Rewrite it again

Future perspectives---write as recommendation and it is very long

What about the ethical approval statement

References

Some cited references need to be more updated

Huge number of references were used—61—why

|Some journal names were written abbreviated, while others were not—why same style should be

All references should be rewritten again

There are no gross figures/images?

Author Response

Comment 1: Conclusion and recommendations are more than enough.

Response 1: We thank the reviewer for their positive comment and kind appreciation of our work. We are pleased that the conclusion and recommendations are found to be sufficient.

 

Comment 2: It is very long paper without any need.

Response 2: We thank the referee for this observation. We appreciate the concern regarding the manuscript’s length. We have revised the paper to improve conciseness by removing redundancies. Changes are highlighted in red color.

 

Comment 3:There is no simple summary or running title.

Response 3: We thank the reviewer for highlighting this omission. A concise summary and an appropriate running title have now been added to the revised manuscript to enhance clarity and accessibility.

 

Comment 4:Huge numbers of abbreviations were detected, it is better to create a separate table for this.

Response 4: We have included a separate abbreviation table in our modified manuscript. Changes are highlighted in red color.

 

Table 1: List of abbreviations used in the manuscript, along with their full forms and brief descriptions for clarity.

Abbreviation

Full name

MPXV

Monkeypox virus

PNA

Peptide nucleic acids

SNPs

Single nucleotide polymorphisms

CRISPR

Clustered Regularly Interspaced Short Palindromic Repeats

GAGs

Glycosaminoglycans

IMVs

Intracellular mature virions

IEVs

Intracellular enveloped virions

EEVs

Extracellular enveloped virions

MPXVRCC

Monkeypox virus rapid and reliable diagnostic platform, termed

 RPA

Recombinase polymerase amplification

 MPXV-CA and MPXV-WA

MPXV Central African and MPXV west African

SCOPE

Streamlined CRISPR On-Pod Evaluation

 ADA

Adenosine deaminase

CDA

Cytosine deaminase

ASOs

Antisense oligonucleotides

RNAi

RNA interference

TPOXX

Tecovirimat

SMIs

Small-molecule inhibitors

 mAbs

Monoclonal antibodies

25-HC

25-hydroxycholesterol

IFN

Type I interferon

 

Comment 5:Abstract :There are no highlights added after the abstract.

Response 5: We thank the reviewer for this comment. However, highlights are not required according to the journal’s guidelines, and therefore have not been included in the manuscript.

 

Comment 6:There is no graphical abstract.

Response 6: As per reviewer’s suggestion, we have included a graphical abstract here.

 

Comment 7:What is/are the creativity of this work.

Response 7: We thank the reviewer for this important question.Although this is a review article where we discuss existing approaches and propose biomaterial-driven strategies for combating MPXV infection.The novelty of this work lies in its integrated overview of multiple advanced therapeutic strategies against monkeypox virus (MPXV) within a single framework. It uniquely highlights the combined potential of synthetic oligonucleotides, nanoparticles, small molecules, and biomimetic scaffolds for effective antiviral intervention. The study further emphasizes the role of biocompatible biomaterials in reducing side effects, improving drug delivery, and enhancing vaccine performance. Additionally, it proposes the future integration of emerging technologies such as CRISPR and mRNA-based systems to strengthen MPXV treatment and prevention.

 

Comment 8:LN/27-28---Avoid usage of some words, already used with the main topic as keywords.

Response 8: We thank the reviewer for this helpful suggestion. We have revised the text to minimize repetition of keywords and improved the wording for better clarity and readability.

 

Comment 9:Tabulate all abbreviations.

Response 9: As per reviewer’s suggestion, we make tabulate all abbreviations. It is included in our modified manuscript.

 

Comment 10:LN/20—CRISPR—detailed then abbreviate—clarify its role also.

Response 10: We have included detailed CRISPR, and abbreviation in our modified manuscript.

Comment 11:LN/24—nanocarriers—detailed this /how.

Response 11: We thank the reviewer for this comment. The term “nanocarriers” has been removed from the revised manuscript to improve clarity.

 

Comment 12:Abstract is very short—expand your data.

Response 12: We thank the reviewer for the comment. We elaborated our abstract as per suggestion. Changes are highlighted in red color.

 

Comment 13:Add some words like backgrounds/aims/methods/conclusion and recommendations.

Response 13: We have included background/aims/methods/conclusion in our modified manuscript.

 

Comment 14:Add nanotechnology/differential diagnosis/molecular pathways/vaccination to the keywords.

Response 14: We have included as per suggestion.

 

Comment 15: LN/32/40/57/61/88--add references

Response 15: We have included as per suggestion.

 

Comment 16: LN/32—zoonotic infection—describe changes related to both humans and animals /methods of diagnosis.

Response 16: We thank the reviewer. We have included this portion as per suggestion.

 

Comment 17:LN/54-55—readjust it

Response 17:We have readjusted this.

 

Comment 18: LN/55—surg—what?

Response 18: We have modified this sentence.

 

Comment 19:  MPXV—pathogenesis/molecular pathogenesis /treatment should be enclosed with an updated reference.

Response 19: We have updated the reference as per suggestion.

 

Comment 20: What about MPXV mutation stressors/mode/avoidance?

Response 20: We have included and highlighted in red color.

 

Comment 21: Introduction should be more concise.

Response 21: We have made our introduction portion more concise. Changes are highlighted in red color.

 

Comment 22: Novelty should be more clarified.

Response 22: We have clarified the novelty as per suggestion.

 

Comment 23: Aims should be more highlighted.

Response 23: Although it is a review article, we have clarified and highlighted aim of our review in the abstract portion.

 

Comment 24: LN/100—endocytosis---how.

Response 24: We have explained that endocytosis occurs through membrane-associated molecules, particularly glycosaminoglycans (GAGs), such as heparan sulfate and chondroitin sulfate.Changes are highlighted in our modified manuscript in red color.

 

Comment 25: LN/100—more details are requested/transcription machinery---its role in induction of the disease in chart.

Response 25: We have explained details of transcription machinery. Changes are highlighted in red color.

 

Comment 26: LN/105/109—add reference.

Response 26:We have included references.

 

Comment 27: LN/109—what about MPXV—inclusion bodies and its role in the diagnosis (differential diagnosis).

Response 27:We have included inclusion bodies and their role in the diagnosis.

 

Comment 28: LN/113-114—molecular pathogenesis is requested.

Response 28: Since our review article is not directly related to molecular pathogenesis, we have removed “molecular pathogenesis” in our modified manuscript.

 

Comment 29: LN/123-124---more details about mechanism/each in chart.

Response 29: We include mechanism in the figure caption. (at LN/123-124)

 

Comment 30: LN/131/154/156/159/169—add references.

Response 30: We have included the respective references for LN/131/154/156/159/169.

 

Comment 30: Huge numbers of abbreviations were detected, it is better to create a separate table for this.

Response 30: We thank the reviewer. As per suggestion, we make a separate table for abbreviations and included in our modified manuscript.

 

Comment 31:LN.148—2 different styles of writing references were observed---same style should be –apply for all.

Response 31: Thank you to the reviewer for pointing out our mistake. We have corrected reference errors in the modified manuscript.

Comment 32:LN/154—detailed this.

Response 32: We have removed this portion to make better clarity of the manuscript.

 

Comment 33:LN/169—how would be modified.

Response 33: CRISPR can target the MPXV gene. CRISPR-Cas9 functions as a double-strand DNA cleavage system that enables precise gene targeting and disruption. This is the mechanism to modify the genomic DNA (MPXV).

 

Comment 34:What about the MPXV pathology.

Response 34: We have briefly added MPXV pathology in our introduction portion. MPXV pathology involves viral replication in host cells leading to tissue damage, immune evasion, and characteristic lesions due to inflammation and cell death. Changes are highlighted in red color.

 

Comment 35:What about the clinical signs/symptoms.What about the PM lesions.Are there any recorded mortalities—what percent.

Response 35: We thank the reviewer for this valuable comment. We have revised the manuscript to include a brief overview of the clinical signs and symptoms of Mpox, clarified the description of PM lesions, and added information on reported mortality rates. These changes are highlighted in the revised manuscript.

 

Mpox typically presents with both systemic and dermatological features, including early symptoms such as fever, headache, myalgia, fatigue, and notably lymphade-nopathy, which helps distinguish it from similar infections. Within a few days, char-acteristic skin lesions develop and progress through stages such as macules, papules, vesicles, pustules, and finally crusts, commonly affecting the face, extremities, and anogenital region. Pseudomembranous (PM) lesions are relatively uncommon and may occur on mucosal surfaces such as the oropharynx or genital areas, appearing as whit-ish or yellowish membrane like patches due to epithelial damage, inflammation, and necrosis, and may be associated with pain, dysphagia, or secondary infections. The re-ported mortality rate varies depending on the viral clade and outbreak setting, gener-ally ranging from less than 1% in recent outbreaks to approximately 10% in historically reported cases.

 

Comment 36:Conclusion. More than enough. 3-4 sentences are considered.Rewrite it again.

Response 36: We modified the conclusion more precisely in our modified manuscript. Changes are highlighted in red color.

 

Comment 37: Future perspectives---write as recommendation and it is very long.

Response 37: We modified future perspectives briefly, and precisely as per reviewer’s suggestion.

 

Comment 38:What about the ethical approval statement.

Response 38: Since this is a review article and we don’t perform any animal/human experiments, we assume that ethical approval is not necessary here.

 

Comment 39:References:Some cited references need to be more updated.Huge number of references were used—61—why? Some journal names were written abbreviated, whileothers were not—why same style should beAll references should be rewritten again.There are no gross figures/images?

Response 39: We have modified the references as per suggestion.

Reviewer 2 Report

Comments and Suggestions for Authors

The Monkeypox virus (MPXV) meets the urgent need for new generation therapeutics beyond traditional antiviral treatment. The CRISPR-based systems inhibit replication, and antisense oligonucleotides or peptide nucleic acids (PNAs) through cleaving MPXV DNA. The authors provided a vital review focusing on a tile, namely, small-molecule antivirals toward key MPXV enzymes can be potentially delivered via nanocarriers. Their review provides interesting information for drug development toward biomaterial-driven strategies aimed at combating MPXV infection. Overall, the authors performed a good review. Recommending that their work can be accepted after minor revision.

  1. Figure 2 shows the Monkeypox virus (MPXV) life cycle, the binding of MPXV to host cell receptors is a restarting point. The authors had better clarify how they bind to each other.
  2. In antiviral drugs-based approach to combat MPXV, the authors focused on the roles of small molecules, the authors should performed a more detailed discussion on those molecules listed at Figure 5 so that their work can be better understood.
  3. In their abstraction, the authors should mention how many fields are used to perform their review so that the readers understand main contents through their abstraction.
  4. Inhibiting or holding back the replication of the VP37 protein has an antiviral effect and the authors performed a deeper discussion on the corresponding mechanism.

Author Response

Comment 1: The Monkeypox virus (MPXV) meets the urgent need for new generation therapeutics beyond traditional antiviral treatment. The CRISPR-based systems inhibit replication, and antisense oligonucleotides or peptide nucleic acids (PNAs) through cleaving MPXV DNA. The authors provided a vital review focusing on a tile, namely, small-molecule antivirals toward key MPXV enzymes can be potentially delivered via nanocarriers. Their review provides interesting information for drug development toward biomaterial-driven strategies aimed at combating MPXV infection. Overall, the authors performed a good review. Recommending that their work can be accepted after minor revision.

Response 1: We appreciate reviewer constructive comment here. We have further modified our manuscript to better understandof the readers.

 

Comment 2: Figure 2 shows the Monkeypox virus (MPXV) life cycle, the binding of MPXV to host cell receptors is a restarting point. The authors had better clarify how they bind to each other.

Response 2: Thank you to reviewer for his comment here. We have modified our manuscript. Below is the precious explanation included in the main manuscript highlighting in red color.The Monkeypox virus (MPXV) binds to host cells through membrane-associated molecules, particularly glycosaminoglycans (GAGs) such as heparan sulfate and chondroitin sulfate. These are widely present on cell surfaces. These act as initial attachment receptors, allowing the virus to anchor to the host cell.

 

Comment 3:In antiviral drugs-based approach to combat MPXV, the authors focused on the roles of small molecules, the authors should perform a more detailed discussion on those molecules listed at Figure 5 so that their work can be better understood.

Response 3: We thank the reviewer for this valuable suggestion. We have revised the manuscript to include a more detailed discussion of the small molecules presented in Figure 5, elaborating on their mechanisms of action, efficacy, and relevance in combating MPXV. These additions improve the clarity and overall understanding of the antiviral drug-based approach, and all changes have been highlighted in the revised manuscript.

 

LAVR-289 targets the viral DNA polymerase (insert 2 domain), inhibiting early-stage replication in the cytoplasm. It shows high potency against multiple orthopoxviruses, including the 2022 MPXV clade IIb variant, at nanomolar levels, and demonstrates significant efficacy in animal models by reducing mortality and viral load.25, 70 UMM-766 is a nucleoside analog that inhibits orthopoxvirus replication, including Mpox, and shows effective oral activity in animal models with reduced viral load and protection against severe disease.71 Trifluridine (TFT) is an FDA-approved topical anti-viral used for ocular mpox infections, where it inhibits viral DNA replication and helps prevent complications, and it is often used alongside Tecovirimat in severe or resistant cases.72 TO427 is a computationally identified small-molecule inhibitor targeting the VP39 methyltransferase of Mpox, disrupting viral mRNA capping and replication. It shows higher potency than standard inhibitors, but remains a preliminary candidate requiring further experimental validation.73 FC-6407 is an experimental inhibitor of the D4 DNA processivity factor in Mpox, disrupting viral DNA replication by destabilizing the protein, with an ICâ‚…â‚€ of about 13.4 μM.25 Atovaquone is a repurposed antiparasitic drug that inhibits Mpox replication at a post-entry stage by targeting dihydroorotate dehydrogenase (DHODH), thereby reducing viral DNA and virion pro-duction, with higher potency than cidofovir.74 Atovaquone, mefloquine, and mol-nupiravir are various small molecules identified as effective against monkeypox virus (MPXV), exhibiting anti-MPXV activity with 50% inhibitory concentrations ranging from 0.51 to 5.2 μM, surpassing the potency of cidofovir.75, 76 Molnupiravir inhibits viral replication through lethal mutagenesis and shows strong in vitro activity. However, its clinical effectiveness may be limited, and it remains an experimental repurposed candidate without established use for mpox.74

 

Comment 4: In their abstraction, the authors should mention how many fields are used to perform their review so that the readers understand main contents through their abstraction.

Response 4: We modified our abstract highlighting particular therapeutic fields targeting MPXV. We hope that readers can easily understand the main contents through abstract. Changes are highlighted in red color.

 

Comment 5:Inhibiting or holding back the replication of the VP37 protein has an antiviral effect and the authors performed a deeper discussion on the corresponding mechanism.

Response 5: We appreciate to the reviewer for his positive comment here. We hope readers will achieve deep understanding on VP37 mechanistic pathway reading our review article.

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript addresses an important and timely topic, namely emerging therapeutic strategies against monkeypox virus (MPXV), with emphasis on antiviral agents, oligonucleotide-based approaches, CRISPR-related concepts, and combination strategies. The topic is potentially suitable for a review article because MPXV remains of considerable scientific and public health interest, and the attempt to connect virology with advanced therapeutic technologies is valuable.
However, in its current form, the manuscript has substantial conceptual, structural, and editorial weaknesses that limit its scientific value. The main concern is that the paper is framed as a review on biomaterial-based therapeutic strategies, but much of the text discusses general antiviral concepts, diagnostics, viral biology, and speculative future interventions rather than biomaterials in a rigorous and organized way. In addition, the manuscript is insufficiently critical, often descriptive, and at times overly speculative. The language also requires major editing, as numerous grammatical, syntactic, and terminological issues reduce clarity and weaken the manuscript’s credibility. Overall, the manuscript would require major revision before it could be considered for publication.

Major issuess:
1. The title and abstract suggest that the article is specifically about biomaterial-based therapeutic strategies. However, the manuscript does not clearly define what is meant by “biomaterial-based” approaches, nor does it systematically organize the review around biomaterials as a core conceptual axis. Large sections focus on general virology, antiviral drugs, CRISPR diagnostics, and hypothetical molecular strategies, rather than on biomaterial platforms, delivery systems, scaffolds, nanocarriers, or other clearly delineated biomaterial-enabled therapeutics. As a result, the manuscript reads more like a broad review of possible MPXV interventions than a focused review on biomaterial-based therapy. This conceptual mismatch should be addressed.

2. Section 3.1 is presented as “CRISPR based antiviral approaches,” but much of the discussion concerns CRISPR-based diagnostic systems for MPXV detection rather than therapeutic genome targeting. This creates conceptual confusion. Diagnostic CRISPR platforms may be highly relevant to MPXV management, but they should either be moved to a separate section or clearly distinguished from antiviral treatment strategies. In the current version, the review conflates detection and therapy in a way that weakens its structure.

3. The manuscript frequently uses forward-looking and speculative phrasing such as “we envisioned,” “can be applied,” or “will be efficient,” especially in relation to CRISPR genome editing, deaminase-based editing, ASO/PNA therapeutics, and biomimetic/nanoplatform strategies. These concepts may indeed be promising, but the review often presents them with stronger confidence than is justified by the evidence discussed. Review articles should maintain a stricter distinction between demonstrated findings and future possibilities.

4. The current organization does not provide a coherent analytical framework. The paper would benefit from a clearer structure, for example:
- MPXV biology and therapeutic targets
- biomaterial-enabled delivery platforms
- oligonucleotide therapeutics and nanocarriers
- small molecules and formulation strategies
- combination therapies and translational challenges
- current limitations and future directions
At present, the review reads as a sequence of loosely connected topics rather than a critically synthesized field overview.

5. Certain claims appear overstated or insufficiently nuanced. For instance, the discussion of MPXV mutation rate and the implied sustained effectiveness of vaccines and antivirals is too categorical. Similarly, some mechanistic descriptions, including parts of the SNP discussion and sections on viral enzymes, would benefit from more precise wording and stronger linkage to supporting evidence.

6. The conclusion states that biomaterials “will ensure minimal side effects” and are “adaptable, scalable, and suitable” for global MPXV challenges. Such claims are too strong for a review built largely on emerging, preclinical, or hypothetical approaches. The conclusion should be rewritten in a more cautious and evidence-based manner.

Author Response

Comment 1:This manuscript addresses an important and timely topic, namely emerging therapeutic strategies against monkeypox virus (MPXV), with emphasis on antiviral agents, oligonucleotide-based approaches, CRISPR-related concepts, and combination strategies. The topic is potentially suitable for a review article because MPXV remains of considerable scientific and public health interest, and the attempt to connect virology with advanced therapeutic technologies is valuable.However, in its current form, the manuscript has substantial conceptual, structural, and editorial weaknesses that limit its scientific value. The main concern is that the paper is framed as a review on biomaterial-based therapeutic strategies, but much of the text discusses general antiviral concepts, diagnostics, viral biology, and speculative future interventions rather than biomaterials in a rigorous and organized way. In addition, the manuscript is insufficiently critical, often descriptive, and at times overly speculative. The language also requires major editing, as numerous grammatical, syntactic, and terminological issues reduce clarity and weaken the manuscript’s credibility. Overall, the manuscript would require major revision before it could be considered for publication.

Response 1: We appreciate reviewer’s constructive comment to improve our manuscript. We have improved our manuscript addressing reviewer’s suggestions. Changes are highlighted in red color in our modified manuscript.

 

Comment 2: The title and abstract suggest that the article is specifically about biomaterial-based therapeutic strategies. However, the manuscript does not clearly define what is meant by “biomaterial-based” approaches, nor does it systematically organize the review around biomaterials as a core conceptual axis. Large sections focus on general virology, antiviral drugs, CRISPR diagnostics, and hypothetical molecular strategies, rather than on biomaterial platforms, delivery systems, scaffolds, nanocarriers, or other clearly delineated biomaterial-enabled therapeutics. As a result, the manuscript reads more like a broad review of possible MPXV interventions than a focused review on biomaterial-based therapy. This conceptual mismatch should be addressed.

Response 2: We thank you for your nice comments. We agree that there is conceptual mismatch of the manuscript title with its content. Therefore, we modified and broadened our manuscript title. In addition, we modified our review abstract to represent a possible MPXV intervention.  Changes are highlighted in red color in our modified manuscript.

 

Comment 3: Section 3.1 is presented as “CRISPR based antiviral approaches,” but much of the discussion concerns CRISPR-based diagnostic systems for MPXV detection rather than therapeutic genome targeting. This creates conceptual confusion. Diagnostic CRISPR platforms may be highly relevant to MPXV management, but they should either be moved to a separate section or clearly distinguished from antiviral treatment strategies. In the current version, the review conflates detection and therapy in a way that weakens its structure.

Response 3: We completely agree with the reviewer’s comment. As per your suggestion, we have removed irrelevant portions in section 3.1. It removes conceptual confusion and makes it more appropriate for the readers.Changes are highlighted in red color.

 

Comment 4: The manuscript frequently uses forward-looking and speculative phrasing such as “we envisioned,” “can be applied,” or “will be efficient,” especially in relation to CRISPR genome editing, deaminase-based editing, ASO/PNA therapeutics, and biomimetic/nanoplatform strategies. These concepts may indeed be promising, but the review often presents them with stronger confidence than is justified by the evidence discussed. Review articles should maintain a stricter distinction between demonstrated findings and future possibilities.

Response 4: We completely agree with the reviewer’s comment. We have toned down our confidence regarding future perspective in the CRISPR section. Changes are highlighted in the red color in our modified manuscript.

 

Comment 5: The current organization does not provide a coherent analytical framework.The paper would benefit from a clearer structure, for example:
- biomaterial-enabled delivery platforms
- oligonucleotide therapeutics and nanocarriers
- small molecules and formulation strategies
- combination therapies and translational challenges
- current limitations and future directions
At present, the review reads as a sequence of loosely connected topics rather than a critically synthesized field overview.

Response 5: We have modified our review structure as per reviewer’s suggestion here.

 

Comment 6: Certain claims appear overstated or insufficiently nuanced. For instance, the discussion of MPXV mutation rate and the implied sustained effectiveness of vaccines and antivirals is too categorical. Similarly, some mechanistic descriptions, including parts of the SNP discussion and sections on viral enzymes, would benefit from more precise wording and stronger linkage to supporting evidence.

Response 6: We agree with reviewer statement here. We have removed the overstated sentences and make it more precise for readers. All changes are highlighted in red color.

 

Comment 7: The conclusion states that biomaterials “will ensure minimal side effects” and are “adaptable, scalable, and suitable” for global MPXV challenges. Such claims are too strong for a review built largely on emerging, preclinical, or hypothetical approaches. The conclusion should be rewritten in a more cautious and evidence-based manner.

Response 7: Thank you to the reviewer for minutely checking our manuscript and pointing out our strong statements in the conclusion portion. In accordance with the reviewer's feedback, we have toned down our claims, adopting a more evidence-based, cautious tone in the conclusion. We hope this modified portion will satisfy this reviewer. All the changes are highlighted in the main manuscript.

 

We portray how various therapeutic strategies can be effective to combat the monkeypox virus (MPXV) especially synthetic oligonucleotides (PNAs/short oligos/deaminase), nanoparticles, small molecules (targeted to viral protein/polymerase enzyme), and various biomimetic scaffolds. The biocompatible nature of synthetic platforms may be effective for minimal side effects, inhibition of viral transmission, and overcoming challenges like viral resistance in human system. In addition, biomaterials can support vaccine development by stabilizing antigens and improving immune response, offering a strong defense against outbreaks. We hope that these strategies can be suitable for handling MPXV-related global health challenges, especially in underserved regions around the globe. Combination of biomaterials with innovative technologies like mRNA or gene-editing tools could further strengthen MPXV treatment and prevention with further research advancement in near future.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

 Accepted

Reviewer 3 Report

Comments and Suggestions for Authors

The authors have adequately addressed my comments and revised the manuscript accordingly. I believe that, in its current form, the article is suitable for publication.

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