Review Reports

Comments 1: The review article by Xiaodan Wu et al., titled "Smart nanoformulations for local anesthetics: A new generation of drug delivery systems," delivers an extensive overview of the literature on intelligent delivery systems for local anesthetics, focusing specifically on the transition from passive carriers to responsive RTDDS platforms that are activated by external stimuli such as NIR, ultrasound, and magnetic fields. This topic is timely, especially in the context of exploring alternatives to opioids and advancing the notion of "on-demand analgesia."

In the reviewer's view, the manuscript is well-organized and addresses a significant clinical issue; however, in its current form, it is overly descriptive and does not offer a sufficiently critical and technical analysis of the translational limitations and risks associated with specific types of materials. For the work to be considered for publication, the authors need to address the following major comments:

The Introduction of the manuscript does not adequately specify how this review is distinct from the many previous publications in the area of long-acting/controllable local anesthesia, including studies from leading research groups. It is important to clarify the knowledge gap being addressed, whether it pertains to a comparison of triggering mechanisms, an assessment of materials and their safety, or an exploration of translational barriers. Furthermore, the authors should outline the key take-home messages they wish to convey, such as which platforms are considered most promising and the reasons for this evaluation.]

Response 1: We fully agree with this assessment and have substantially revised the Introduction to address these concerns. We analyzed existing reviews in this field and found that most can be categorized into three types. (1) General overviews of various formulation types (liposomes, polymeric nanoparticles, lipid complexes), which are primarily descriptive in scope; (2) Reviews focusing on clinical postoperative pain management, but lacking a materials science perspective; (3) In-depth analyses of single technologies, yet unable to facilitate cross-platform comparisons. Despite these significant contributions, there is a lack of systematic discussions from the perspective of triggering mechanisms.

The revised paragraph is as follows:

“Given the substantial research achievements in the field of LAs, numerous review articles have systematically summarized advances in nanoparticle formulations for pain management. These prior publications primarily focused on the administration routes, animal models, and evaluation methods of local anesthetic delivery systems [24]. Additional studies have explored carrier systems with varying sizes and structural morphologies, such as nanocapsules and nanospheres [25]. Local anesthetic delivery systems based on natural polymers have also garnered significant attention [26]. Relevant reviews encompass experimental validation, animal studies, and clinical trials, with particular emphasis on hydrogel and bupivacaine formulations [27, 28]. Despite these significant contributions, there is a lack of systematic discussions from the perspective of triggering mechanisms. Existing reviews have not systematically compared the roles of different triggering modes in LAs formulations, nor have they thoroughly evaluated their mechanisms of action, material safety, or systematically analyzed core barriers hindering clinical translation.” – page 2, paragraph 3, and line 75.

We have now revised the manuscript to more explicitly articulate this positioning and unique contribution in the Introduction sections.

Comments 2: Regarding systems that utilize gold nanorods (GNRs), the discussion should be broadened to include surface chemistry and the preparation process of the material for biological applications. From a translational perspective, the residual presence of surfactants used in synthesis and the effectiveness of their removal and stabilization methods—like ligand exchange, PEGylation, and protective coatings—may be crucial. A brief, critical analysis of which approaches effectively minimize the risk of cyto-/neurotoxicity is requested, along with an indication of the safety data necessary for perineural administration.

Response 2: Thank you for your insightful and detailed comment regarding the discussion of GNRs-based systems. We fully agree that surface chemistry, preparation processes, surfactant residue, detoxification strategies, and neurotoxicity considerations are critical for clinical translation. We fully acknowledge the critical importance of surface chemistry, preparation techniques, surfactant residues, detoxification strategies, and neurotoxicity considerations for clinical translation.

To this end, we have substantially expanded the relevant sections, including: (1) Detailed elaboration on the toxicity of dodecyl sulfate sodium (CTAB) during the synthesis process; (2) An evaluation of detoxification methods to assess their efficacy in reducing neurotoxicity while preserving GNRs functionality; and (3) A comprehensive overview of safety data for peripheral nerve delivery, including what safety assessments should encompass. We believe these additions substantially enhance the translational perspective of our review. The revised sections have been incorporated into the manuscript and are clearly marked for your review. 

“Surface engineering and biosafety of gold nanorods remain critical challenges. The surfactant cetyltrimethylammonium bromide (CTAB), essential for the classical seed-mediated growth method, constitutes a core obstacle to their clinical translation [79]. While CTAB's bilayer structure confers colloidal stability to GNRs, its cytotoxicity (membrane lysis, ROS induction) and hemolytic effects preclude direct in vivo application. Consequently, any biomedical GNRs must undergo thorough surface modification to replace or shield CTAB. Surface modification strategies include ligand exchange (e.g., mPEG-SH substitution), polymer coating (e.g., polyethylene glycolization), inorganic shell coating (e.g., silica), and lipid bilayer modification. Polyethylene glycolation is currently the most widely adopted method, reducing protein adsorption, extending circulation half-life, and partially shielding CTAB toxicity by forming a steric hindrance layer [80]. However, PEGylation struggles to achieve complete CTAB displacement; residual CTAB may become encapsulated beneath the PEG layer or at the GNR tips, posing a non-negligible risk of long-term slow leakage. In contrast, silica coating physically isolates and completely encapsulates CTAB. CTAB can be extracted during coating, yielding toxicity data significantly superior to PEGylated GNRs. However, thickening the silica shell (>10 nm) may weaken localized surface plasmon resonance effects, and the mechanical mismatch between the rigid shell and neural tissue warrants caution[81].

Significant gaps remain in the current safety data required to advance GNRs toward clinical applications in the perineural setting. The biodistribution of GNRs following perineural administration is an often-overlooked issue, as nanoparticles may be transported retrograde along the intraneuronal lymphatic system or axoplasm to the spinal cord, posing a risk of central nervous system exposure. Therefore, claims of “biocompatibility” based solely on cell viability data are wholly inadequate. Safety evaluation must extend beyond conventional cell viability assays. An ideal assessment system should encompass: (1) electrophysiological function (nerve conduction velocity, compound action potentials); (2) myelin integrity (MBP immunostaining, transmission electron microscopy); (3) long-term tissue response (chronic inflammation, fibrosis); (4) Axonal transport and central exposure risk [82]. Unfortunately, most studies were confined to short-term cell experiments, with minimal coverage of these critical indicators [83]. This review argues that bionic membrane encapsulation strategies combining CTAB complete shielding, tissue mechanical compatibility, and long-term stability represent a key future development direction for neuroperipheral GNRs systems.” – page 9, paragraph 6, and line 366.

Comments 3: The authors suitably bring attention to the matter of long-term safety and clearance pathways at a general level; nonetheless, the dialogue is not sufficiently detailed for specific material classes (e.g., HMON, CuS, GNR). It is advisable to broaden the discussion to encompass the potential retention and fate of particles post-perineural administration, the risk of chronic inflammatory responses (e.g., granuloma formation), and the effects of particle size/shape and degradation on long-term persistence.

Response 3: Thank you for your valuable comments regarding long-term safety and clearance pathways. We fully agree that the original manuscript lacked in-depth analysis specific to particular material categories. In the revised version, we have systematically addressed the fate of particles and safety requirements following neuroperipheral administration, using gold nanorods (GNRs) as an exemplar.

“Significant gaps remain in the current safety data required to advance GNRs toward clinical applications in the perineural setting. The biodistribution of GNRs following perineural administration is an often-overlooked issue, as nanoparticles may be transported retrograde along the intraneuronal lymphatic system or axoplasm to the spinal cord, posing a risk of central nervous system exposure. Therefore, claims of “biocompatibility” based solely on cell viability data are wholly inadequate. Safety evaluation must extend beyond conventional cell viability assays. An ideal assessment system should encompass: (1) electrophysiological function (nerve conduction velocity, compound action potentials); (2) myelin integrity (MBP immunostaining, transmission electron microscopy); (3) long-term tissue response (chronic inflammation, fibrosis); (4) Axonal transport and central exposure risk [82]. Unfortunately, most studies were confined to short-term cell experiments, with minimal coverage of these critical indicators [83]. This review argues that bionic membrane encapsulation strategies combining CTAB complete shielding, tissue mechanical compatibility, and long-term stability represent a key future development direction for neuroperipheral GNRs systems.” – page 10, paragraph 2, and line 385.

Comments 4: The review lacks comprehensive discussion regarding the formation of protein corona on nanocarriers upon exposure to biological fluids. This process can significantly change the physicochemical properties of particles and influence their stability and in vivo behavior. It is recommended to incorporate a subsection or paragraph that details how corona formation may impact the release profile and the reproducibility of the on-demand effect in in vivo conditions.

Response 4: Thank you for your valuable insights regarding the protein corona. We concur that the formation of the protein corona upon contact with biological fluids is a critical determinant of nanocarrier behavior in vivo, and its omission represents a significant oversight. Accordingly, we have added a dedicated chapter (4.3.4. The Effect of Protein Corona on Triggered Drug Release) that comprehensively addresses the following:

(1) The fundamental process of protein corona formation (including hard and soft corona) when nanocarriers are exposed to interstitial fluid after perineural injection, with emphasis on the unique protein composition of the perineural microenvironment.

(2) The specific mechanisms by which the protein corona influences trigger-release curves, including alterations in the physicochemical properties of the nanocarrier (e.g., particle size, surface charge, surface chemistry, optical properties), internal chemical triggers, or enzyme recognition sites, thereby affecting its behavior in drug release.

(3) Current research limitations and future directions.

We believe this newly added section significantly enhances the manuscript's quality by addressing a major biological hurdle in clinical translation.

“The regulation of drug release from nanoformulations depends not only on their intrinsic properties but also on the influence of the target environment. Upon injection into the body and contact with bodily fluids, the surface of nanocarriers rapidly adsorbs proteins from interstitial fluid and plasma, forming a dynamic layer known as the “protein corona”. This process occurs within seconds to minutes and is virtually unavoidable [114]. First, high-abundance proteins (albumin, immunoglobulins, fibrinogen) adsorb to form a “soft corona”. Over time, low-abundance, high-affinity proteins gradually displace them (Vroman effect), forming a “hard corona” [115]. Nanocarriers for regional anesthesia are typically injected around nerves, where these areas are rich in extracellular matrix proteins (collagen, laminin, fibronectin) and inflammation-related proteins (if tissue damage is present). The protein crown formed by these proteins alters the physicochemical properties of the nanocarriers, including particle size, surface charge, surface chemistry, and optical properties. More importantly, the protein coat can form an additional diffusion barrier, delaying drug release [116].

The interference of protein coronas with various triggering mechanisms cannot be overlooked. For external physical triggers, such as photothermal materials represented by gold nanorods, the formation of protein coronas alters the surface properties of nanoparticles, thereby affecting their photothermal conversion efficiency. Bionic modifications mimicking red blood cell membranes have been proven to effectively neutralize surface charges on nanoparticles and improve colloidal stability, indirectly confirming the significant impact of protein coronas on surface properties [117]. For internal chemical triggers, the buffering capacity of the protein coat may attenuate local pH changes, delaying the response of pH-sensitive carriers. Simultaneously, the protein coat may obscure enzyme recognition sites or neutralize trigger enzymes through inhibitors within the coat. Mucin-derived protein coats have been shown to mask, displace, and weaken the active targeting effects of transferrin-modified nanoparticles [118]. More intractably, protein coat formation is a dynamic process exhibiting substantial interindividual variability: patient-specific variables (biological sex, genetic background, disease state, age) directly influence coat composition and behavior; disease states (e.g., diabetes, cancer) alter circulating proteomes, leading to coat composition differences; and the protein composition of the neuroperipheral microenvironment varies by injection site and tissue injury severity [119]. This implies that two patients injected with the same batch of trigger-induced local anesthetic nanoparticle formulations may exhibit entirely different release behaviors due to individual variations in protein crowns. This irreproducibility represents one of the key obstacles to the clinical translation of trigger-induced nanoparticle formulations.

Most trigger-release studies have been validated only in simple buffers, lacking release data in protein-containing media. Protein corona research has predominantly focused on intravenous administration, with minimal attention to the “tissue fluid protein corona” in local delivery. Recent perspectives emphasize that protein corona formation in local delivery (e.g., mucosal tissues) differs significantly from systemic administration, yet relevant studies remain extremely limited [120]. Systematic investigations into trigger efficiency and the structure-function relationship of protein coronas are particularly scarce [121]. Future research should advance in the following directions: establish physiologically relevant release media and validate trigger-release performance at least in systems containing serum or tissue homogenates; develop anti-protein corona strategies such as dense PEG layers or biomimetic membrane coatings; conduct personalized protein corona prediction by integrating patient proteome data to establish predictive models for trigger efficiency; and most critically, perform specialized studies on the neural microenvironment to elucidate its unique protein corona formation characteristics. Existing research indicates that the development of neuropathy is closely linked to protein-coated immunorecognition [122]. Only through deep understanding and active regulation of protein coats can trigger-based local anesthetic nanomedicines truly transition from “in vitro concept” to “in vivo reliability.”” – page 14, paragraph 1, and line 566.

Comments 5: Figure 1 functions as a conceptual schematic; however, in its current iteration, it is too simplified and requires enhancement to satisfy the standards of a technical review. Please standardize the terminology and clearly differentiate between traditional carriers and responsive/triggered systems, in addition to improving the legend and stimulus descriptions.

Response 5: Thank you for your constructive feedback regarding Figure 1. We agree that the original conceptual diagram was overly simplified and did not adequately meet the standards expected for a technical review. To address this concern and enhance reader comprehension, we have made the following revisions. We have created a new Figure 1 titled “Schematic diagram of the scope and structure of this review.” This Figure provides a comprehensive visual overview, clearly illustrating the structure of the review and elucidating the logical flow from traditional models to trigger/response systems.

“For clarity, Figure 1 provides an overview of the scope and logical framework of this review. Beginning with the established clinical roles of local anesthetics, the diagram illustrates the evolutionary path toward smart nanomedicines, key trigger mechanisms and delivery platforms currently under investigation, and the ultimate goal of establishing rational design principles for clinical translation.

Figure 1. Schematic diagram of the scope and structure of this review. This figure illustrates the logical framework of the review. Starting from existing clinical local anesthetics, it progresses to traditional nanomedicines, and ultimately forms smart nanoformulations responsive to external stimuli. The focus highlights carrier platforms and triggering mechanisms, as well as biological targets and challenges in clinical translation. The ultimate goal is to establish rational design principles to facilitate the clinical translation of on-demand analgesia.”– page 3, paragraph 1, and line 102.

We have strengthened the main text to clearly distinguish between conventional carriers and responsive/trigger-based systems. 

“These formulations lacking trigger-release capabilities are termed traditional LAs nanoformulations.”– page 5, paragraph 2, and line 188.

We believe these modifications transform Figure 1 from a simple schematic into a technically accurate, information-rich visual representation. It effectively guides readers through the scope and structure of this review while maintaining professional standards. The revised figure and legend have been incorporated into the manuscript and clearly marked for your review.

Thank you for helping us enhance the clarity of this manuscript.

Comments 6: The manuscript's section on hydrogels lacks discussion regarding the mechanical conditions at the administration site (micromotion, compression, friction, perineural environments) and how these factors might impact gel integrity and the release profile. Please address the in situ stability (e.g., rheology, resistance to deformation) and the risk of uncontrolled burst release.

Response 6: Thank you very much for your valuable feedback. You pointed out that the section on hydrogels in the manuscript did not sufficiently discuss how mechanical conditions at the delivery site affect hydrogel integrity and release profiles, and requested additional discussion on field stability and the risk of uncontrolled rapid release. As a review article, we should indeed provide a more systematic overview of research progress in this field rather than merely describing material design superficially. Following your suggestions, we have incorporated this content into the revised manuscript (4.1. Core Delivery Systems: Why are Gels an Ideal Platform?), providing a comprehensive commentary on this topic. The specific revisions are as follows.

“When constructing hydrogel systems, it is essential to comprehensively consider the mechanical microenvironment at the delivery site, the hydrogel's resistance to deformation, and how mechanical forces influence the release profile. The administration site of LAs (joint cavity, subcutaneous tissue, perineural space, or between muscle and fascia) is situated within a complex dynamic mechanical environment. This primarily includes micro-movements, compressive loads, tissue sliding friction, and pulsatile compression around nerves. Mechanical factors influence hydrogel integrity and drug release behavior. Micro-movements and friction manifest around joints or nerves, where relative tissue sliding imposes shear stress on hydrogels. Insufficient interfacial adhesion may cause gel-tissue separation or even fragmentation. Research indicates that hydrogels undergo gel-sol phase transitions at shear stresses of approximately 9.04 Pa in most tissues. Therefore, the constructed nanomedicine formulations should meet this mechanical parameter [65]. Additionally, in weight-bearing areas or regions subjected to muscular compression, hydrogels require sufficient compressive modulus to maintain their three-dimensional network structure. Repeated compressive loading may induce network fatigue and microcrack formation, thereby accelerating drug diffusion [66]. Finally, the perineural environment presents unique challenges. Neural tissues are highly sensitive to compression and exhibit significant gliding range. If hydrogels form envelopes around nerves, their stiffness must match that of neural tissues to prevent compression injuries.

Hydrogels prepared as RTDDS should possess suitable rheological properties and deformation resistance. For instance, the hydrogel remains in a dissolved state at 10°C but rapidly gels within 30 seconds at the average human body temperature of 37°C [67]. LAs require administration via syringe, and can be delivered through in situ gelation, wherein the hydrogel forms in response to physiological stimuli after injection. Another approach is shear thinning, where hydrogels exhibit non-Newtonian fluid behavior. During injection, they demonstrate reduced viscosity under high shear rates, yet rapidly regain mechanical strength once shear stress is removed. For such shear-thinning systems, viscosity must remain below 1 Pa to ensure smooth injection [68].

Mechanically regulated drug release mechanisms, including pore compression, network deformation, shear-induced release, and force-induced bond cleavage, should be incorporated into nanodrug delivery design. These principles can be leveraged to engineer mechanoresponsive drug delivery systems, such as “on-demand” hydrogels that accelerate drug release with increased movement intensity. The mechanical microenvironment also poses risks of uncontrolled release. When hydrogels exhibit insufficient fatigue resistance, repeated stress loading may cause macroscopic fragmentation, dramatically increasing exposed surface area. Insufficient adhesion at the gel-tissue interface can lead to debonding under micro-movements, forming leakage pathways for drugs. Degradation-induced mechanical property decline may cause hydrogels to prematurely reach yield points, resulting in structural instability [69].”– page 8, paragraph 3, and line 288.

4. Response to Comments on the Quality of English Language

Point 1: The English could be improved to more clearly express the research.

Response 1: We have revised the manuscript to address the grammatical and syntactical issues and have improved the language throughout for better clarity and precision.

5. Additional clarifications

We extend our thanks to the editor and reviewers for their diligent work and helpful feedback during the peer-review process.

Comments 1: The review by Ke et al. addresses an actual and interesting topic. Although for most parts it is well written and discussed, it can be significantly improved before acceptance to meet the high-quality standards of Pharmaceutics.

When I reviewed the manuscript, the following questions and comments came up.

1) The title of this review should be modified to reflect the issues being addressed; somehow, the current title does not fully match with the entire review scope.

Response 1: Thank you for your suggestion regarding the title revision. After careful consideration, we have modified the title to: “Design and Application of Intelligent Local Anesthetic Nanoformulations.”

This revised title more accurately captures the dual focus of our paper: material design aspects (including surface engineering, detoxification strategies, and triggering mechanisms) alongside considerations for translational applications (safety, protein corona, mechanical stability, and clinical barriers). We believe this title is concise, clear, and accessible to readers across various disciplines.

The revised title has been incorporated into the manuscript and clearly marked for your review. Thank you again for your valuable input.

Comments 2: 2) Table 1 has to be reformulated to include additional information, including the studies that bring the main limitations/achievements and References are also missing.

Response 2: Thank you for your constructive feedback regarding Table 1. We agree that the previous version lacks sufficient detail and proper referencing. In response, we have completely reformulated Table 1 to include the following additional information. The revised Table 1 has been incorporated into the manuscript (page 6, paragraph 2, and line 225.) with all references updated accordingly. We believe this reformulation significantly enhances the table's utility as a quick-reference tool for readers while maintaining the critical perspective that characterizes our review.

Comments 3: 3) Figure 1 is very interesting and focused, but it does not show what kind of nanoformulations can be employed. This information should be included in the figure or in the caption.

Response 3: Thank you for your insightful comments regarding Figure 1. We fully agree that readers require a comprehensive visual overview of the nanoparticle formulations discussed throughout the review. To address this, we have added a new Figure 1 that concisely illustrates the scope and structure of the entire review.

This clearly displays the primary types of nanocarriers, providing readers with an intuitive roadmap to facilitate smooth navigation through the manuscript. The original figure comparing different release modes has been renumbered as Figure 2 and retains its position as a key conceptual illustration.

We believe the new Figure 1 provides the comprehensive overview of nanomedicines you requested, while Figure 2 retains its role as a clear conceptual comparison of release mechanisms. Together, they significantly enhance reader comprehension. The revised figures have been incorporated into the manuscript and clearly marked for your review.

Thank you for this valuable suggestion.

Comments 4: 4) The sub-topic 4.3.4 is confusing; some sentences are not connected. It must be deeply revised, and it would be beneficial if the authors could present some clear examples to elucidate the topic.  

Response 4: Agree. Thank you for your critical observation regarding subsection 4.3.4. We agree that the current version suffers from disconnected sentences and lacks clarity. In response, we have completely rewritten this subsection with a clearer logical flow and added concrete examples to illustrate each key point.

We believe this revised subsection is now clear, well-structured, and effectively illustrates the concept through carefully chosen examples. The rewritten subsection has been incorporated into the manuscript and is clearly marked for your review.

“4.3.5. Strategies for Multi-Responsive Systems

To navigate the complex in vivo environment and achieve precise control, integrating multiple triggering logics into a single platform represents a frontier research area. Multi-responsive systems can be designed using two distinct operational modes, including "AND-gate" logic (requiring simultaneous stimuli) and "sequential" logic (requiring programmed order of stimuli).  

Systems can be designed where release requires the simultaneous presence of two stimuli. For instance, a nanocarrier might only release its payload in the presence of both mild heat (from a photothermal effect) and a slightly acidic pH (found in inflamed tissues). This AND-gate logic dramatically enhances targeting specificity and safety [123]. In tumor research, it functions as an AND logic gate, requiring both low pH and esterase to be present simultaneously for the release of antitumor drugs. This dual-condition activation ensures that payload release is strictly confined to the specific areas, minimizing systemic exposure.

More advanced systems utilize one stimulus to initiate or activate the carrier, while another stimulus triggers the actual release process. This allows complex, programmable delivery regimens unattainable with a single trigger, paving the way for truly adaptive analgesic therapies [124]. For instance, drugs can be locally released or confined in a gel state through thermal triggering, with subsequent remote modulation of release rates enabled by externally triggered ultrasound modulation. Based on this principle, multi-response systems hold particular promise. It is even possible to design nanoformulations with triple responsiveness to pH, NIR, and temperature, coordinating multiple stimuli to achieve precise spatial and temporal control.

For the delivery of LAs, multi-response systems offer unique advantages. For instance, a “AND-gate” design can require simultaneous fulfillment of near-infrared light exposure and pH conditions to trigger analgesic effects, ensuring drug release only when and where needed. Additionally, sequential systems may first use an initial magnetic field to guide nanoparticles to target nerves, followed by ultrasound-triggered release for on-demand pain control. These concepts can be directly applied to designing smarter, safer perineural delivery systems for postoperative pain management.” – page 15, paragraph 2, and line 622.

Thank you for guiding us to improve the clarity and impact of this important section.

Comments 5: 5) The credits on the figures' creation are missing. This information must be included.  

Response 5: Agree. All figures in the manuscript have been checked, and appropriate credit information has been included in the respective figure legends. These modifications are clearly marked in the revised manuscript.

Comments 6: 6) A scheme showing what kind of new materials or new delivery systems could be conceived or a representation of how disruptive new ideas/concepts can turn into applicable devices, must be added to potentiate the translational claim of the review.  

Response 6: To address this, we have added a new Figure 1 that concisely illustrates the scope and structure of the entire review.

This clearly displays the primary types of nanocarriers, providing readers with an intuitive roadmap to facilitate smooth navigation through the manuscript. The original figure comparing different release modes has been renumbered as Figure 2 and retains its position as a key conceptual illustration.

We believe the new Figure 1 provides the comprehensive overview of nanomedicines you requested, while Figure 2 retains its role as a clear conceptual comparison of release mechanisms. Together, they significantly enhance reader comprehension. The revised figures have been incorporated into the manuscript and clearly marked for your review.

Thank you for this valuable suggestion.

Comments 7: 7) Manuscript needs to be corrected in terms of the English language and Grammar.  

Response 7: Agree. We have revised the manuscript to address the grammatical and syntactical issues and have improved the language throughout for better clarity and precision.

4. Response to Comments on the Quality of English Language

Point 1: Manuscript needs to be corrected in terms of the English language and Grammar.

Response 1: We have revised the manuscript to address the grammatical and syntactical issues and have improved the language throughout for better clarity and precision.

5. Additional clarifications

We extend our thanks to the editor and reviewers for their diligent work and helpful feedback during the peer-review process.