Nanotechnology-Based Strategies for Hair Regeneration: Mechanistic Insights and Translational Perspectives for Androgenetic Alopecia

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Below are my specific observation on the manuscript entitled “Nanotechnology-Based Strategies for Hair Regeneration: Mechanistic Insights and Translational Perspectives for Androgenetic Alopecia”. Addressing these concerns would improve the manuscript quality.

1. While the manuscript is thorough, several recent reviews have already addressed nanotechnology-based approaches for AGA (e.g., refs. 48, 49, 55, 71). The authors should more clearly articulate what distinguishes this review from existing literature. Please explicitly state the unique contribution of this article (e.g., stronger emphasis on microenvironment remodeling, nanozyme-based systems, or translational roadmaps).
2. Although multiple mechanisms (oxidative stress, angiogenesis, inflammation, stem cell activation) are discussed, many sections remain descriptive. Where possible, the authors should deepen the mechanistic discussion (e.g., how specific nanomaterial properties influence Wnt/β-catenin signaling or dermal papilla cell behavior). Clarify whether the reported effects are primarily direct (cell–nanomaterial interactions) or indirect (drug delivery–mediated).
3. The manuscript highlights impressive preclinical efficacy (e.g., >90% hair regeneration coverage in mouse models), but the clinical relevance of these metrics is not sufficiently contextualized. The authors should more critically discuss the limitations of rodent AGA models and the risk of overestimating translational potential. Please clarify whether any nano-enabled systems discussed have entered arly-phase clinical trials, even outside AGA (e.g., dermatology or wound healing).
4. Section 6 touched safety concerns, but the discussion remains relatively high-level. The authors are encouraged to discuss specific toxicological risks associated with commonly used nanomaterials (e.g., metal nanozymes, inorganic nanoparticles). Consider adding examples of reported adverse effects or regulatory setbacks from dermatological nanomedicine to provide a more balanced perspective.
5. The manuscript refers to “nano-cosmeceuticals” and therapeutic systems somewhat interchangeably. Please clarify how the authors distinguish cosmetic, cosmeceutical, and pharmaceutical nano-formulations in the context of AGA. This distinction is critical for regulatory pathways and should be more explicitly addressed.
6. Manuscript would benefit from adding a Table indicating patent disclosures on Nanotechnology-Based Strategies for Hair Regeneration.
7. Also, addition of a table mentioning ongoing of completed clinical trials (if available) on “Nanotechnology-Based Strategies for Hair Regeneration” would increase manuscript weightage. If even only 1-2 such studies are available, can be mentioned within the text. Authors can search trials from: https://clinicaltrials.gov/.
8. Term “Nano-enabled” and “nanotechnology-based” are used interchangeably; consider standardizing terminology.
9. Overall, the English language quality is good, but some sentences are overly long and could be streamlined for clarity. For example but not limited to page 6 section 5: “Yang et al reported that a quercetin-encapsulated and polydopamine-integrated nanosystem (PDA@QLipo) was developed to remodel the perifollicular microenvironment and initiate hair follicle regeneration for AGA treatment.” Authors can reframe and correct the sentence.
10. The conclusion largely reiterates earlier sections. Consider adding a concise forward-looking statement identifying one or two priority directions for the field.
11. Title of reference 49 should be in title case.

Comments on the Quality of English Language

Overall, the English language quality is good, but some sentences are overly long and could be streamlined for clarity. For example but not limited to page 6 section 5: “Yang et al reported that a quercetin-encapsulated and polydopamine-integrated nanosystem (PDA@QLipo) was developed to remodel the perifollicular microenvironment and initiate hair follicle regeneration for AGA treatment.” Authors can reframe and correct the sentence.

Author Response

We sincerely thank the Editor and the reviewers for their careful evaluation of our manuscript and for the constructive and insightful comments. We have revised the manuscript thoroughly in response to all comments, which has significantly improved its clarity, methodological rigor, and overall quality. Below, we provide a point-by-point response to each comment. All changes have been incorporated into the revised manuscript.

 

Reviewer #1

We would like to express our sincere appreciation for your thorough and insightful review. Your suggestions regarding the clinical relevance of rodent models, the distinction between cosmeceuticals and pharmaceuticals, and the toxicological risks of nanomaterials have been instrumental in enhancing the critical depth of our manuscript.

We have addressed each of your concerns as follows:

 

1. While the manuscript is thorough, several recent reviews have already addressed nanotechnology-based approaches for AGA (e.g., refs. 48, 49, 55, 71). The authors should more clearly articulate what distinguishes this review from existing literature. Please explicitly state the unique contribution of this article (e.g., stronger emphasis on microenvironment remodeling, nanozyme-based systems, or translational roadmaps).

 

Response:

We appreciate that several comprehensive reviews on hair regeneration exist. Nevertheless, our manuscript offers a distinct perspective by highlighting “Microenvironment Remodeling” and “Active Nanozymes” as central mechanisms driving hair follicle regeneration, rather than focusing solely on conventional drug delivery.

Accordingly, in the Introduction, we have added the following statement: “Unlike previous reviews (e.g., refs 48, 55) that primarily emphasize the delivery of FDA-approved drugs, this article focuses on the rational design of multifunctional nanomaterials (e.g., nanozymes) that actively modulate the oxidative and inflammatory niches within the hair follicle.” This emphasis on mechanistic, nanotechnology-based microenvironmental interventions differentiates our work and provides novel insights for the field.

 

2. Although multiple mechanisms (oxidative stress, angiogenesis, inflammation, stem cell activation) are discussed, many sections remain descriptive. Where possible, the authors should deepen the mechanistic discussion (e.g., how specific nanomaterial properties influence Wnt/β-catenin signaling or dermal papilla cell behavior). Clarify whether the reported effects are primarily direct (cell–nanomaterial interactions) or indirect (drug delivery–mediated).

Response:

We agree that a deeper mechanistic analysis is needed.

1) We have expanded Section 5. Specifically, we now discuss how the intrinsic antioxidant properties of metal nanozymes (e.g., Ni-Cu) directly scavenge ROS in dermal papilla cells, thereby preventing the inhibition of Wnt/β-catenin signaling by oxidative stress. We clarify that these are "direct cell-nanomaterial interactions" rather than just drug delivery.

 

“To elucidate how nanotechnology actively remodels the hair follicle niche, it is essential to distinguish direct material-cell interactions from conventional drug-mediated effects. Metallic nanozymes, such as Ni-Cu bimetallic nanoparticles, exhibit intrinsic SOD and CAT mimetic activity. Upon internalization by dermal papilla cells, they efficiently scavenge ROS, suppressing p38 MAPK-mediated overexpression of DKK-1, stabilizing β-catenin, and promoting transcription of hair-growth genes like AXIN2 and LEF1. Unlike minoxidil, which indirectly stimulates hair growth via vasodilation, these nanotechnology-based interventions directly modulate DPC signaling, maintaining the anagen state through catalytic bioactivity. This paradigm shift highlights a transition from passive drug carriers to active, signaling-modulatory bionanomaterials for AGA therapy.”

 

3. The manuscript highlights impressive preclinical efficacy (e.g., >90% hair regeneration coverage in mouse models), but the clinical relevance of these metrics is not sufficiently contextualized. The authors should more critically discuss the limitations of rodent AGA models and the risk of overestimating translational potential. Please clarify whether any nano-enabled systems discussed have entered arly-phase clinical trials, even outside AGA (e.g., dermatology or wound healing).

 

Response:

We appreciate this insightful comment regarding the translational gap between preclinical success and clinical reality.

• We have added a critical discussion in Section 7 regarding the physiological differences between rodent models and human scalp skin, specifically addressing why "90% hair regeneration" in mice often overestimates human outcomes. Additionally, we also explicitly discuss the differences in hair follicle cycling (synchronized vs. mosaic), skin thickness, and the absence of a true androgen-dependent miniaturization process in most rodent models.

 

“While the reported preclinical efficacy-often exceeding 90% hair follicle recovery in rodent models-is highly encouraging, these metrics must be interpreted with caution. Rodent models, such as C57BL/6 mice, possess a highly synchronized hair cycle and a thinner dermis, which inherently overestimate the penetration efficiency and therapeutic impact of nanomaterials. Unlike the mosaic growth pattern and deep-seated follicular bulbs (3-5 mm) of the human scalp, rodent follicles are superficial and more accessible to topical nanosystems. Consequently, rapid regeneration in mice may reflect an accelerated telogen-to-anagen transition rather than a true reversal of androgen-driven follicular miniaturization. To bridge this gap, current research is pivoting toward human hair follicle organoids and ex vivo scalp skin models to provide more clinically relevant data.”

 

• We have updated the manuscript to include Table 4, which summarizes clinical trials of nanotechnology-based systems in AGA (e.g., liposomal finasteride and MSC-derived exosomes). Furthermore, we have highlighted the clinical success of similar nanoplatforms in related dermatological fields (e.g., nano-emulsions for actinic keratosis and nanocrystalline silver for wound healing) to support the feasibility of this technology.

 

Table 4. Ongoing or Completed Clinical Trials for Nanotechnology and Advanced AGA Therapies.

 

4. Section 6 touched safety concerns, but the discussion remains relatively high-level. The authors are encouraged to discuss specific toxicological risks associated with commonly used nanomaterials (e.g., metal nanozymes, inorganic nanoparticles). Consider adding examples of reported adverse effects or regulatory setbacks from dermatological nanomedicine to provide a more balanced perspective.

Response:

We sincerely appreciate the reviewer’s constructive feedback regarding the safety and toxicological evaluation of nanotechnology-based therapies. We agree that a more granular discussion of potential risks is essential for a balanced perspective.

Accordingly, we have significantly revised Section 6 to address these specific concerns. The additions include:

• We have introduced a detailed discussion on the systemic translocation of inorganic nanomaterials. Specifically, we highlight how metal-based nanozymes (e.g., CeO₂, Au) can persist in the mononuclear phagocyte system (liver and spleen), posing potential risks of chronic organotoxicity.
• To provide a realistic view of clinical translation, we have added examples of regulatory hurdles. This includes the discussion of "pseudo-allergies" and proinflammatory responses sometimes induced by lipid-based platforms due to surfactants or oxidation products, which can lead to clinical trial suspensions.
• We have further emphasized the complexity of reproducibility and quality control in nanomaterial manufacturing, calling for standardized characterization protocols and interdisciplinary collaboration to navigate regulatory pathways.

 

The following text has been incorporated into the revised manuscript:

 

“Although the follicular route enables targeted delivery, it may also facilitate systemic translocation, raising specific concerns for inorganic nanomaterials. Metal-based nanozymes, such as cerium oxide (CeO₂) or gold (Au) nanoparticles, can persist in the mononuclear phagocyte system, especially the liver and spleen, posing risks of chronic organotoxicity. Even seemingly biocompatible platforms, such as lipid-based nanoparticles, have encountered regulatory hurdles due to unforeseen proinflammatory responses or “pseudo-allergies” induced by surfactants or lipid oxidation products. These events can exacerbate the microenvironment they aim to modulate, occasionally leading to trial suspension.

Variability in nanomaterial composition, manufacturing, and formulation further complicates reproducibility, quality control, and regulatory assessment. These challenges underscore the need for standardized characterization protocols, comprehensive long-term toxicological studies, and well-defined regulatory pathways, implemented through systematic preclinical validation and interdisciplinary collaboration.”

5. The manuscript refers to “nano-cosmeceuticals” and therapeutic systems somewhat interchangeably. Please clarify how the authors distinguish cosmetic, cosmeceutical, and pharmaceutical nano-formulations in the context of AGA. This distinction is critical for regulatory pathways and should be more explicitly addressed.

 

Response:

We fully agree with the reviewer that a clear distinction between these categories is critical for understanding regulatory pathways. We have updated Section 7 to explicitly define and differentiate these three categories based on their target tissue, biological impact, and regulatory requirements.

 

“To navigate the associated regulatory landscapes, nano-formulations must be categorized by their intended use: nano-cosmetics target non-living hair fibers for aesthetic enhancement; nano-cosmeceuticals are "borderline" products containing bioactive components that influence follicle physiology under less stringent cosmetic regulations; and nano-pharmaceuticals are disease-oriented systems requiring rigorous Phase I–III validation and adherence to FDA/EMA standards. Clarifying these distinctions is essential for aligning nanomaterial design with specific clinical and regulatory objectives.”

6. Manuscript would benefit from adding a Table indicating patent disclosures on Nanotechnology-Based Strategies for Hair Regeneration. Also, addition of a table mentioning ongoing of completed clinical trials (if available) on “Nanotechnology-Based Strategies for Hair Regeneration” would increase manuscript weightage. If even only 1-2 such studies are available, can be mentioned within the text. Authors can search trials from: https://clinicaltrials.gov/.

Response:

We sincerely appreciate the reviewer’s constructive suggestion to include patent and clinical trial data. We agree that these additions significantly enhance the manuscript's granularity regarding the translational potential and commercial maturity of nanotechnology-based therapies.

We have incorporated two new tables to provide a comprehensive overview of the current technological and clinical landscape:

 

• Table 3 (Representative Patent Disclosures): This table summarizes key patentscovering innovative nano-enabled hair regeneration strategies, including bimetallic nanozyme applications, specialized liposomal formulations, and dissolvable microneedle delivery systems.

Table 3. Representative Patent Disclosures for Nanotechnology-based Hair Regeneration Strategies.

 

• Table 4 (Clinical Trial Progress): A systematic summary of ongoing and completed trials retrieved from ClinicalTrials.gov (as of Feb 2026) has been added. This includes critical data on liposomal finasteride and MSC-derived exosomal therapies, highlighting the active transition of these nanoplatforms from bench to bedside.

Table 4. Ongoing or Completed Clinical Trials for Nanotechnology-based and Advanced AGA Therapies.

 

These additions provide the necessary context to substantiate the clinical relevance of nanotechnology in AGA management, as requested.

 

7. Term “Nano-enabled” and “nanotechnology-based” are used interchangeably; consider standardizing terminology.

Response:

Thanks for your professional suggestion. Accordingly, we have standardized the term " nanotechnology-based " throughout the text.

 

8. The conclusion largely reiterates earlier sections. Consider adding a concise forward-looking statement identifying one or two priority directions for the field.

 

Response:

We thank the reviewer for the suggestion to strengthen the forward-looking nature of our conclusion. We agree that a robust summary should not only synthesize current progress but also delineate high-impact trajectories for the next generation of AGA management.

The Conclusion section has been significantly updated. We have identified and discussed two strategic priority directions that are poised to redefine the field over the next decade:

 

“The employment of nanotechnology-based strategies has led to substantial advancements in the treatment of AGA, primarily by facilitating efficient follicular targeting, controlled drug release, and active modulation of the follicular microenvironment. Rather than serving solely as delivery vehicles, emerging nanotechnology-based platforms increasingly address key pathogenic drivers of AGA, including oxidative stress, inflammation, impaired angiogenesis, and stem cell niche dysfunction. However, the future impact of nanotechnology in AGA therapy will depend on the development of more intelligent, mechanism-oriented treatment paradigms rather than incremental improvements in delivery efficiency alone.

In the forthcoming period, it is anticipated that two priority directions will determine the subsequent phase of development in this field. Firstly, the utilization of AI in the design of multi-targeted nanozymes presents a compelling strategy for the engineering of single nanoplatforms capable of simultaneously regulating redox balance, inflammatory signaling and vascular support. This approach aims to more effectively address the multifactorial nature of follicular miniaturization. Secondly, the advent of personalized nano-therapy, predicated on scalp microbiome and niche analysis, portends the imminent realization of precision trichology. In this paradigm, responsive nanosystems are meticulously tailored to individual microbial and inflammatory profiles, thereby ensuring on-demand therapeutic release that is characterized by enhanced efficacy and safety.

The integration of nanotechnology, AI, and personalized biology offers a compelling framework for the future management of AGA. The translation of next-generation nanotechnology-based therapies into clinical practice will be contingent on sustained interdisciplinary collaboration, complemented by advances in scalable manufacturing and regulatory alignment.”

 

9. Overall, the English language quality is good, but some sentences are overly long and could be streamlined for clarity. For example but not limited to page 6 section 5: “Yang et al reported that a quercetin-encapsulated and polydopamine-integrated nanosystem (PDA@QLipo) was developed to remodel the perifollicular microenvironment and initiate hair follicle regeneration for AGA treatment.” Authors can reframe and correct the sentence.

Response:

We thank the reviewer for the suggestion to reframe and correct the sentence. Accordingly, we have revised the sentence of

“Yang et al reported that a quercetin-encapsulated and polydopamine-integrated nanosystem (PDA@QLipo) was developed to remodel the perifollicular microenvironment and initiate hair follicle regeneration for AGA treatment.”

to

“Yang et al. developed PDA@QLipo, a quercetin-encapsulated nanosystem designed to promote hair regeneration. This platform functions by remodeling the perifollicular microenvironment and effectively mitigating localized oxidative stress.”

 

10. Title of reference 49 should be in title case.

Response:

We sincerely apologize for the formatting error in the bibliography. Reference 49 has been corrected from the previous all-caps format to the standard Title Case.

Additionally, we have performed a thorough manual audit of the entire reference list to ensure that:

• All titles follow the consistent capitalization style required by Biomedicines.
• All author names and journal abbreviations are standardized.
• Any other "all-caps" or "sentence-case" inconsistencies have been rectified.

 

“Kayal, P., et al., Nanocarrier-Based Approaches for Enhanced Management of Androgenetic Alopecia: Advancements and Future Prospects. 2025. 17(3): p. 13-27.”

 

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

Dear editor,

I have reviewed the manuscript titled ‘Nanotechnology-Based Strategies for Hair Regeneration: Mechanistic Insights and Translational Perspectives for Androgenetic Alopecia’. Author tried to compile the nanocarrier based formulations for treatment of AGA. But authors have not compiled the recent information instead they presented only thorough overview. Hence, manuscript need to write with scientific temperament outcomes. To improve the manuscript, some suggestions and comments are provided.

Introduction: Precise temporal and spatial regulation of signaling pathways-including Wnt/β-catenin, Sonic hedgehog (Shh), transforming growth factor-β (TGF-β), and bone morphogenetic protein (BMP) signalingis essential for maintaining normal hair follicle homeostasis and sustaining hair shaft production [6-12]. Write separate reference for each signal pathways. Check the manuscript for such type of sentences.

All figures are looking like AI generated. What software used to make the figures?

Table 1 and 2. References are not added. Need to add the references.

3. Nanocarrier-Based Drug Delivery Systems for AGA: elaborate this section for each nanocarriers such as liposomes, ethosomes, transethosomes, exosomes, nanoparticles (polymeric and lipid based), nanoemulsion, microemulsion etc for AGA development with their important outcomes in terms of physicochemical and preclinical or clinical. Add table with respect of drug or natural compound, type of formulation, particle size and zeta, animal model, outcomes, references for AGA development.
4. Nano-Enabled Microneedle Systems for Transdermal Follicular Delivery: add table with recently developed microneedle based on preclinical studies for AGA treatment.

Notwithstanding the encouraging……………………………………………………… reliable and sustainable clinical translation of nanotechnology enabled therapies for AGA. No references added.

Add separate section of ‘recent nanocarriers based patents for AGA treatment’ and clinical trials completed and under trial.

Modified the conclusion after revision.

 

Comments on the Quality of English Language

Scientific English editing is required.

Author Response

We sincerely thank the Editor and the reviewers for their careful evaluation of our manuscript and for the constructive and insightful comments. We have revised the manuscript thoroughly in response to all comments, which has significantly improved its clarity, methodological rigor, and overall quality. Below, we provide a point-by-point response to each comment. All changes have been incorporated into the revised manuscript.

 

 

 

Reviewer #2

We are deeply grateful for your meticulous review and constructive suggestions. We acknowledge that the original version leaned toward a thematic overview; hence, we have thoroughly revised the manuscript to incorporate specific "scientific temperament outcomes," including detailed physicochemical parameters, preclinical data, and patent/clinical trial analyses.

Our point-by-point responses are as follows:

 

1. Introduction: Precise temporal and spatial regulation of signaling pathways-including Wnt/β-catenin, Sonic hedgehog (Shh), transforming growth factor-β (TGF-β), and bone morphogenetic protein (BMP) signaling is essential for maintaining normal hair follicle homeostasis and sustaining hair shaft production [6-12]. Write separate reference for each signal pathways. Check the manuscript for such type of sentences.

 

Response:

We sincerely thank the reviewer for this meticulous suggestion. We agree that assigning specific references to each signaling pathway provides better clarity and academic precision.

• We have re-organized the sentence in the Introduction to link each signaling pathway directly to its corresponding authority references (References 6-12).
• Following the reviewer’s advice, we have conducted a comprehensive audit of the entire manuscript to identify and rectify any similar "clustered citations," ensuring that all specific biological mechanisms are supported by their respective individual references.

"Precise temporal and spatial regulation of signaling pathways-including Wnt/β-catenin [6, 11], Sonic hedgehog (Shh) [9, 10], transforming growth factor-β (TGF-β) [8], and bone morphogenetic protein (BMP) [7, 8, 11] signaling-is essential for maintaining normal hair follicle homeostasis and sustaining hair shaft production [10, 12]."

 

2. All figures are looking like AI generated. What software used to make the figures?

 

Response:

We would like to formally clarify and assure the reviewer that all illustrations and schematic diagrams included in this manuscript (Figures 1-5) are original works conceptualized and designed by the authors.

To ensure scientific accuracy and aesthetic consistency across the manuscript, the professional design platform BioRender.com was utilized. We hold a valid professional license that grants us the necessary permissions to create, edit, and publish these original designs in peer-reviewed journals. We would like to emphasize that no AI-based generative image tools were used; instead, all figures were manually constructed using standardized biological vector components to accurately represent the specific scientific mechanisms and follicular structures discussed in this review.

3. Table 1 and 2. References are not added. Need to add the references.

Response:

Thanks for the professional suggestion. Accordingly, we have added specific, column-wise references to Table 1 and Table 2 to ensure every claim is traceable to the original literature.

 

4. Nanocarrier-Based Drug Delivery Systems for AGA: elaborate this section for each nanocarriers such as liposomes, ethosomes, transethosomes, exosomes, nanoparticles (polymeric and lipid based), nanoemulsion, microemulsion etc for AGA development with their important outcomes in terms of physicochemical and preclinical or clinical. Add table with respect of drug or natural compound, type of formulation, particle size and zeta, animal model, outcomes, references for AGA development.

 

Response:

We thank the reviewer for this valuable suggestion. In response, we have revised and expanded the section on nanocarrier-based drug delivery systems for AGA to provide a carrier-specific and data-driven discussion covering liposomes, exosomes, polymeric and lipid nanoparticles, with emphasis on their formulation design, key physicochemical properties, and representative preclinical or clinical outcomes.

To systematically consolidate this information, we have revised and expanded Table 1, which now summarizes reported nanocarrier-based AGA formulations, including the drug or natural compound, formulation type, particle size, zeta potential, animal model or clinical setting, therapeutic outcomes, and corresponding references. This structured comparison enables direct cross-platform evaluation and clarifies how physicochemical parameters relate to follicular penetration, bioavailability, and therapeutic efficacy.

 

5. Nano-Enabled Microneedle Systems for Transdermal Follicular Delivery: add table with recently developed microneedle based on preclinical studies for AGA treatment.

Response:

We sincerely thank the reviewer for this suggestion. While we have addressed the overall clinical landscape in Table 4, we agree that a more detailed synthesis of preclinical microneedle (MN) innovations is essential for Section 5.

Instead of a table, we have significantly expanded the text in Section 5 to provide a structured and comprehensive review of recent preclinical breakthroughs. We have categorized these advancements into three key strategic directions:

• Synergistic Delivery: The integration of lipid-based nanocarriers with dissolvable MNs for dual-drug delivery.
• Niche Remodeling: The use of bimetallic nanozymes within MNs to scavenge ROS and modulate the oxidative microenvironment.
• Advanced Bio-platforms: The application of exosome-integrated and stimuli-responsive (pH/light-triggered) MN systems for precision therapy.

By incorporating these concrete examples (e.g., nanozyme-MNs and exosome-hydrogel MNs), we believe the revised Section 5 now offers a much more rigorous and in-depth perspective on the preclinical state-of-the-art in MN-based AGA treatment.

 

6. Notwithstanding the encouraging……………………………………………………… reliable and sustainable clinical translation of nanotechnology enabled therapies for AGA. No references added.

Response:

We sincerely appreciate the reviewer's constructive feedback. We have now substantially revised this section by integrating critical references that address the long-term safety, systemic translocation, immunogenicity, and regulatory hurdles of nanomaterials. Specifically, we have addressed the distinct challenges posed by both inorganic nanozymes and lipid-based platforms to provide a more balanced and evidence-based perspective.

 

“Although the follicular route enables targeted delivery, it may also facilitate systemic translocation, raising specific concerns for inorganic nanomaterials. Metal-based nanozymes, such as cerium oxide (CeO₂) or gold (Au) nanoparticles, can persist in the mononuclear phagocyte system, especially the liver and spleen, posing risks of chronic organotoxicity[144]. Even seemingly biocompatible platforms, such as lipid-based nanoparticles, have encountered regulatory hurdles due to unforeseen proinflammatory responses or “pseudo-allergies” induced by surfactants or lipid oxidation products[145]. These events can exacerbate the microenvironment they aim to modulate, occasionally leading to trial suspension[146].

Variability in nanomaterial composition, manufacturing, and formulation further complicates reproducibility, quality control, and regulatory assessment[147]. These challenges underscore the need for standardized characterization protocols, comprehensive long-term toxicological studies, and well-defined regulatory pathways, implemented through systematic preclinical validation and interdisciplinary collaboration.”

7. Add separate section of ‘recent nanocarriers based patents for AGA treatment’ and clinical trials completed and under trial.

Response:

We sincerely appreciate the reviewer's constructive feedback. Following this suggestion, we have significantly expanded the "Clinical Translation" section by adding two dedicated subsections: Section 7.1 (Patent Landscape for Nanotechnology-based AGA Therapy) and Section 7.2 (Clinical Trials Progress of Nanotechnology-based AGA Therapies).

To provide a structured overview, we have included Table 3 (Representative Patent Disclosures for Nanotechnology-based Hair Regeneration Strategies) and Table 4 (Ongoing or Completed Clinical Trials for Nanotechnology-based and Advanced AGA Therapies). These additions aim to bridge the gap between preclinical innovation and commercial/clinical reality.

The newly added text for these sections is provided below:

“7.1 Patent Landscape for Nanotechnology-based AGA Therapy

The increasing commercial interest in nanotechnology-based hair regrowth solutions is reflected in the diversifying patent landscape, as sumarized in Table 3. Current intellectual property disclosures reveal a strategic shift from simple drug encapsulation toward sophisticated, multi-functional delivery platforms. For instance, recent patents highlight the integration of dissolvable microneedles with lipid-based nanocarriers, designed to overcome the physical barrier of the stratum corneum while ensuring the sustained release of growth factors or anti-androgenic agents directly into the follicular niche.

Furthermore, the patent data underscores a rising trend in bio-inspired systems, particularly those involving exosome-mimetic vesicles and bimetallic nanozymes. These disclosures often focus on unique stabilizing formulations or specific nanoparticle-to-ligand ratios that optimize the scavenging of ROS or the modulation of the Wnt/β-catenin pathway. By protecting specific physicochemical properties-such as precise particle size distributions and surface charge modifications-these patents establish the technical foundations for scaling up manufacturing. Ultimately, the transition from broad-spectrum disclosures to targeted, mechanistically-driven patents in Table 3 signifies the growing maturity of nanotechnology in the competitive AGA therapeutic market.”

“7.2 Clinical Trials Progress of Nanotechnology-based AGA Therapies

As evidenced by the clinical trial progress summarized in Table 4, nanotechnology-based hair loss therapies are undergoing a qualitative leap from "laboratory research" to "clinical translation". These clinical investigations not only validate the high-efficiency delivery capabilities observed in laboratory settings but also confirm the significant advantages of nanoplatforms in enhancing drug bioavailability and reducing systemic side effects within the human environment.

Currently, the focus of clinical translation has shifted from the simple nano-encapsulation of single conventional drugs (such as MXD or finasteride) toward more sophisticated advanced therapies, particularly the synergistic application of exosomes (natural nanovesicles) and microneedle systems. This trend reflects a clinical endorsement of the "microenvironment remodeling" concept: directly regulating oxidative stress, inflammatory status, and angiogenesis around the hair follicle through nano-scale bioactive substances to achieve more sustained hair growth effects than single-agent administration. However, despite the encouraging preliminary results from multiple trials in Table 4, large-scale clinical adoption still faces challenges regarding Good Manufacturing Practice (GMP) standardization, long-term safety monitoring, and the clarification of regulatory classifications. In the future, as more data from Phase III clinical trials are disclosed, nanotechnology is poised to break the deadlock of inconsistent efficacy and poor compliance associated with traditional drugs, driving AGA treatment into a new era of precision medicine and programmed delivery.”

 

8. Modified the conclusion after revision.

Response

We agree with the reviewer that the conclusion should reflect the expanded scope of the revised manuscript. Accordingly, the Conclusion section has been completely rewritten. The updated text now incorporates the new insights gained from our analysis of the patent landscape and clinical trials, while also proposing future directions such as AI-driven nanomedicine and personalized therapy based on the scalp microbiome.

 

The revised Conclusion is as follows:

“The employment of nanotechnology-based strategies has led to substantial advancements in the treatment of AGA, primarily by facilitating efficient follicular targeting, controlled drug release, and active modulation of the follicular microenvironment. Rather than serving solely as delivery vehicles, emerging nanotechnology-based platforms increasingly address key pathogenic drivers of AGA, including oxidative stress, inflammation, impaired angiogenesis, and stem cell niche dysfunction. However, the future impact of nanotechnology in AGA therapy will depend on the development of more intelligent, mechanism-oriented treatment paradigms rather than incremental improvements in delivery efficiency alone.

In the forthcoming period, it is anticipated that two priority directions will determine the subsequent phase of development in this field. Firstly, the utilisation of AI in the design of multi-targeted nanozymes presents a compelling strategy for the engineering of single nanoplatforms capable of simultaneously regulating redox balance, inflammatory signalling and vascular support. This approach aims to more effectively address the multifactorial nature of follicular miniaturisation. Secondly, the advent of personalised nano-therapy, predicated on scalp microbiome and niche analysis, portends the imminent realisation of precision trichology. In this paradigm, responsive nanosystems are meticulously tailored to individual microbial and inflammatory profiles, thereby ensuring on-demand therapeutic release that is characterised by enhanced efficacy and safety.

The integration of nanotechnology, AI, and personalised biology offers a compelling framework for the future management of AGA. The translation of next-generation nanotechnology-based therapies into clinical practice will be contingent on sustained interdisciplinary collaboration, complemented by advances in scalable manufacturing and regulatory alignment.”

9. Scientific English editing is required.

Response

We sincerely apologize for the linguistic inadequacies in the previous version. In accordance with the reviewer’s suggestion, the entire manuscript has undergone comprehensive linguistic revision and professional editing.

 

Specific improvements include:

 

• Terminology Precision: We have refined technical terms to ensure they align with the latest nomenclature in nanotechnology and hair follicle biology (e.g., standardizing terms like "follicular niche," "therapeutic index," and "bioactive nanozymes").
• Scientific Rigor: Sentence structures have been reorganized to enhance the formal and objective tone required for a high-impact scientific review, ensuring a more logical flow between the biological mechanisms and technological applications.
• Grammar and Syntax: A thorough proofreading was conducted to eliminate grammatical errors, improve transitions between sections, and ensure concise expression throughout the text.

 

We believe that the revised manuscript now meets the high standards of scientific English and provides a more rigorous and precise presentation of our findings.

 

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

In this review, the author provides an overview of AGA therapy with a particular emphasis of the nanotechnology as a promising solution to overcome the current limitation of FDA-approved treatments.  While this manuscript is timely and well-structured, it lacks originality, scholarly rigor and sufficient critical depth to warrant publication in its current form.

1. The entitle manuscript largely described the existing knowledge on AGA pathophysiology and nanotechnology-based strategy therapy without proposing the new insights or perspectives that are clearly different from the multiple recent reviews in this field.
2. The author should revise and refine all the figure titles to ensure that the full content presented in each figure are comprehensively and accurately reflected.
3. The discussion on clinical translation, manufacture, and regulatory hurdles is superficial and generical. The concrete examples and available human clinical data should be included.
4. Nano-enabled approaches are not rigorously compared against existing therapies (e.g., optimized topical formulations, oral regimens) using standardized efficacy, safety, or cost-effectiveness metrics.

Author Response

We sincerely thank the Editor and the reviewers for their careful evaluation of our manuscript and for the constructive and insightful comments. We have revised the manuscript thoroughly in response to all comments, which has significantly improved its clarity, methodological rigor, and overall quality. Below, we provide a point-by-point response to each comment. All changes have been incorporated into the revised manuscript.

 

Review 3#

We would like to express our sincere gratitude for your insightful and rigorous critique. Your comments have been invaluable in guiding us to elevate the scholarly rigor and critical depth of this review. The manuscript has undergone substantial revision to extend beyond a mere summary and to provide a more critical, comparative, and translational perspective.

 

1. The entitle manuscript largely described the existing knowledge on AGA pathophysiology and nanotechnology-based strategy therapy without proposing the new insights or perspectives that are clearly different from the multiple recent reviews in this field.

Response:

 

We sincerely thank the reviewer for this critical and constructive feedback. We have carefully re-evaluated our manuscript and recognized the need to more explicitly articulate its unique contributions and novel perspectives compared to recent literature.

In the revised version, we have refined the manuscript to emphasize two primary "new insights" that distinguish this work from previous reviews:

1. Shift from "Passive Delivery" to "Active Niche Modulation": Unlike previous reviews (e.g., [Refs 48, 55]) that primarily emphasize the improved delivery of FDA-approved drugs (Minoxidil and Finasteride), this article focuses on the rational design of multifunctional nanomaterials (such as nanozymes, exosome-mimetics, and bimetallic systems). We highlight their role in actively modulating the oxidative, inflammatory, and vascular niches within the hair follicle microenvironment, rather than merely acting as passive carriers.
2. Integration of Clinical and Patent Landscapes: To provide a perspective that bridges the gap between laboratory research and clinical reality, we have added Section 7.1 (Patent Landscape) and Section 7.2 (Clinical Trial Progress), including Table 3 and Table 4. These sections analyze why many lab-scale successes fail in clinical translation, offering a "commercial-to-clinical" perspective that is often missing in purely mechanistic reviews.
3. Future Paradigms (AI and Precision Trichology): We have significantly updated the Conclusion. Instead of general suggestions, we propose specific future paradigms: the use of AI in the design of multi-targeted nanozymes and the development of personalized nano-therapy based on scalp microbiome analysis.

Specific Revisions in the Manuscript:

• Introduction: Added: “Unlike previous reviews (e.g., refs 48, 55) that primarily emphasize the delivery of FDA-approved drugs, this article focuses on the rational design of multifunctional nanomaterials (e.g., nanozymes) that actively modulate the oxidative and inflammatory niches within the hair follicle.”
• Section 6 & 7: Substantially expanded to include concrete translational hurdles and patent data to move beyond "existing knowledge."
• Conclusion: Completely rewritten to provide mechanism-oriented future paradigms.

We believe these additions clearly differentiate our work as a translational and mechanism-driven roadmap rather than a standard summary of drug delivery systems.

 

2. The author should revise and refine all the figure titles to ensure that the full content presented in each figure are comprehensively and accurately reflected.

 

Response:

We sincerely thank the reviewer for this constructive suggestion. We agree that more descriptive and detailed titles enhance the clarity and academic rigor of the manuscript.

 

Accordingly, all figure titles have been carefully revised and expanded to ensure that the full scope of the content—including specific mechanistic pathways, bioactive design principles, and clinical translational considerations—is comprehensively and accurately reflected. The revised titles are listed below:

Figure 1. Schematic overview of hair follicle anatomy, cycling dynamics, and key pathological alterations associated with AGA.

Figure 2. Classification of nanocarrier-based delivery systems for AGA and their follicular targeting and penetration mechanisms.

Figure 3. Nanotechnology-enabled multimodal remodeling of the follicular microenvironment through regulation of oxidative stress, angiogenesis, and perifollicular inflammation.

Figure 4. Design strategies, structural configurations, and working principles of nanotechnology-based microneedle systems for transdermal follicular delivery.

Figure 5. Translational roadmap of nanotechnology-enabled hair regeneration therapies from material design and preclinical evaluation to clinical application and regulatory considerations

 

3. The discussion on clinical translation, manufacture, and regulatory hurdles is superficial and generical. The concrete examples and available human clinical data should be included.

Response:

We sincerely appreciate the reviewer’s constructive feedback regarding the depth of our translational discussion. We agree that bridging the gap between preclinical innovation and commercial/clinical reality is crucial for this review.

Accordingly, we have completely restructured and expanded Section 7 to include two dedicated subsections that provide concrete evidence of the field’s progress: Section 7.1 (Patent Landscape for Nanotechnology-based AGA Therapy) and Section 7.2 (Clinical Trials Progress of Nanotechnology-based AGA Therapies). These sections are supported by the newly added Table 3 (Patent Disclosures) and Table 4 (Clinical Trials), which offer the "concrete examples" and "human clinical data" requested.

The revised Section 7 is provided below:

“7.1 Patent Landscape for Nanotechnology-based AGA Therapy

The increasing commercial interest in nanotechnology-based hair regrowth solutions is reflected in the diversifying patent landscape, as sumarized in Table 3. Current intellectual property disclosures reveal a strategic shift from simple drug encapsulation toward sophisticated, multi-functional delivery platforms. For instance, recent patents highlight the integration of dissolvable microneedles with lipid-based nanocarriers, designed to overcome the physical barrier of the stratum corneum while ensuring the sustained release of growth factors or anti-androgenic agents directly into the follicular niche.

Furthermore, the patent data underscores a rising trend in bio-inspired systems, particularly those involving exosome-mimetic vesicles and bimetallic nanozymes. These disclosures often focus on unique stabilizing formulations or specific nanoparticle-to-ligand ratios that optimize the scavenging of ROS or the modulation of the Wnt/β-catenin pathway. By protecting specific physicochemical properties-such as precise particle size distributions and surface charge modifications-these patents establish the technical foundations for scaling up manufacturing. Ultimately, the transition from broad-spectrum disclosures to targeted, mechanistically-driven patents in Table 3 signifies the growing maturity of nanotechnology in the competitive AGA therapeutic market.”

“7.2 Clinical Trials Progress of Nanotechnology-based AGA Therapies

As evidenced by the clinical trial progress summarized in Table 4, nanotechnology-based hair loss therapies are undergoing a qualitative leap from "laboratory research" to "clinical translation". These clinical investigations not only validate the high-efficiency delivery capabilities observed in laboratory settings but also confirm the significant advantages of nanoplatforms in enhancing drug bioavailability and reducing systemic side effects within the human environment.

Currently, the focus of clinical translation has shifted from the simple nano-encapsulation of single conventional drugs (such as MXD or finasteride) toward more sophisticated advanced therapies, particularly the synergistic application of exosomes (natural nanovesicles) and microneedle systems. This trend reflects a clinical endorsement of the "microenvironment remodeling" concept: directly regulating oxidative stress, inflammatory status, and angiogenesis around the hair follicle through nano-scale bioactive substances to achieve more sustained hair growth effects than single-agent administration. However, despite the encouraging preliminary results from multiple trials in Table 4, large-scale clinical adoption still faces challenges regarding Good Manufacturing Practice (GMP) standardization, long-term safety monitoring, and the clarification of regulatory classifications. In the future, as more data from Phase III clinical trials are disclosed, nanotechnology is poised to break the deadlock of inconsistent efficacy and poor compliance associated with traditional drugs, driving AGA treatment into a new era of precision medicine and programmed delivery.”

 

4. Nano-enabled approaches are not rigorously compared against existing therapies (e.g., optimized topical formulations, oral regimens) using standardized efficacy, safety, or cost-effectiveness metrics.

Response:

We sincerely appreciate the reviewer’s insightful comment regarding the necessity of benchmarking nano-enabled strategies against gold-standard therapies. We fully agree that a rigorous comparison with established oral and topical regimens is essential for validating clinical utility. Currently, while nano-formulations frequently demonstrate superior follicular bioavailability and a significantly improved safety profile (reduced systemic toxicity) compared to oral regimens, their cost-effectiveness remains a substantial hurdle due to the complexities of specialized manufacturing.

To address this in the revised manuscript, we have expanded our analysis to highlight that while nanotechnology is specifically engineered to circumvent the systemic side effects of conventional treatments, the transition from 'proof-of-concept' to standardized head-to-head clinical comparisons is an evolving priority for the field. We have integrated these comparative metrics into our discussion to provide a more balanced perspective on the strengths and economic challenges of these emerging platforms.

We have added the following text to address the comparative metrics of efficacy, safety, and the clinical rationale for current trial designs:

“Furthermore, as summarized in the clinical trial landscape in Table 4, current investigations of nanotechnology-based therapies for AGA predominantly emphasize the optimization of localized follicular delivery. Accordingly, most trials adopt the established gold-standard topical minoxidil (5%) as the primary active comparator, rather than oral treatment regimens. This trial design reflects the fundamental clinical rationale of nanomedicine. By specifically addressing the systemic toxicity and adverse effects associated with oral therapies—such as sexual dysfunction linked to oral finasteride—nanotechnology-based platforms are primarily evaluated as safer, high-efficacy localized alternatives. Although direct head-to-head comparisons with oral regimens remain limited at current clinical stages, accumulating evidence indicates that nanocarrier systems can significantly enhance the therapeutic index, achieving improved hair density at reduced drug concentrations. Collectively, these findings provide a strong clinical justification for the integration of nanotechnology-based delivery systems into emerging frameworks of precision trichology.”

 

Author Response File: Author Response.docx

Reviewer 4 Report

Comments and Suggestions for Authors

This manuscript is a review of nanotechnology-based strategies for hair regeneration. This area of research is highly relevant, as androgenetic alopecia is a fairly common problem among men and also occurs in women. The authors analyzed the current literature and summarized existing international results in this area. 

The work is interesting, illustrated with bright, clear, and understandable images that schematically demonstrate the processes described. I believe the review is presented at a high level. I didn't have any questions or concerns about the work.

Author Response

We sincerely thank the Editor and the reviewers for their careful evaluation of our manuscript and for the constructive and insightful comments. We have revised the manuscript thoroughly in response to all comments, which has significantly improved its clarity, methodological rigor, and overall quality. Below, we provide a point-by-point response to each comment. All changes have been incorporated into the revised manuscript.

Review 4#

This manuscript is a review of nanotechnology-based strategies for hair regeneration. This area of research is highly relevant, as androgenetic alopecia is a fairly common problem among men and also occurs in women. The authors analyzed the current literature and summarized existing international results in this area. 

The work is interesting, illustrated with bright, clear, and understandable images that schematically demonstrate the processes described. I believe the review is presented at a high level. I didn't have any questions or concerns about the work.

Response

We would like to express our gratitude for the time taken to review our manuscript and for the positive evaluation of the manuscript. We are immensely grateful for your acknowledgement of the scientific caliber and prospective clinical significance of our research, which is a great source of motivation for our research team.

We are appreciative of the commentary provided on the significance of androgenetic alopecia as a persistent clinical challenge for both genders, as well as for acknowledging the importance of nanotechnology in advancing future therapeutic strategies. We would also like to express our gratitude for your favorable evaluation of the schematic illustrations. These were meticulously crafted to elucidate the underlying nanotechnological and biological mechanisms.

In the absence of any specific concerns or requested revisions, the integrity of the sections highlighted in your review has been preserved in the final version of the manuscript. We would like to express our gratitude once more for your constructive evaluation and professional endorsement.

 

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript has been revised and improved significantly by the authors as suggested. Suggested addition of two new sections (7.1 Patent Landscape for Nanotechnology-based AGA Therapy and 7.2 Clinical Trials Progress of Nanotechnology-based AGA Therapies) with two new detailed and informative Tables (Table 3 and 4) has significantly improved the quality of manuscript.  

Reviewer 3 Report

Comments and Suggestions for Authors

Accepted!