Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach

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The advent of nanotechnology, particularly oxygen-delivering nanobubbles (ODNBs), has introduced a promising avenue for enhancing stroke therapy. ODNBs have demonstrated the ability to improve oxygen delivery, enhance therapeutic efficacy, and provide diagnostic advantages through imaging contrast enhancement. However, challenges such as toxicity, off-target effects, and regulatory hurdles must be addressed before clinical translation. This review synthesizes the latest findings on ODNBs in stroke therapy, highlights their key benefits and challenges, and explores future applications, including gene therapy and brain tissue regeneration. By addressing these aspects, this review aims to provide a comprehensive understanding of the potential of ODNBs in revolutionizing stroke treatment." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/14-406", "name": "Review the role of oxygen-delivering nanobubbles in stroke therapy:..." } } ] } Home Browse Review the role of oxygen-delivering nanobubbles in stroke therapy:... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Hamzah H, Suryanti S, Ahmed IA et al. Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach [version 3; peer review: 2 approved] . F1000Research 2025, 14 :406 ( https://doi.org/10.12688/f1000research.162742.3 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Systematic Review Revised Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach [version 3; peer review: 2 approved] Hamzah Hamzah 1 , Suryanti Suryanti https://orcid.org/0009-0008-9978-2511 2,3 , Idris Adewale Ahmed 2 , Bambang Pujo Semedi 4 , Abdullah Machin 4 , Aditya Tri Hernowo 5 Hamzah Hamzah 1 , Suryanti Suryanti https://orcid.org/0009-0008-9978-2511 2,3 , [...] Idris Adewale Ahmed 2 , Bambang Pujo Semedi 4 , Abdullah Machin 4 , Aditya Tri Hernowo 5 PUBLISHED 19 Aug 2025 Author details Author details 1 Universitas Batam, Batam, Riau Islands, Indonesia 2 Lincoln University College, Petaling Jaya, Selangor, Malaysia 3 Universitas Dian Nuswantoro, Semarang, Central Java, Indonesia 4 Universitas Airlangga, Surabaya, East Java, Indonesia 5 Institute Molekul Indonesia, 65151, Indonesia Hamzah Hamzah Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Suryanti Suryanti Roles: Conceptualization, Data Curation, Writing – Original Draft Preparation Idris Adewale Ahmed Roles: Writing – Review & Editing Bambang Pujo Semedi Roles: Project Administration, Validation Abdullah Machin Roles: Investigation, Resources, Visualization Aditya Tri Hernowo Roles: Validation, Visualization OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Nanoscience & Nanotechnology gateway. Abstract Stroke remains a leading cause of mortality and long-term disability worldwide, necessitating innovative therapeutic strategies. The advent of nanotechnology, particularly oxygen-delivering nanobubbles (ODNBs), has introduced a promising avenue for enhancing stroke therapy. ODNBs have demonstrated the ability to improve oxygen delivery, enhance therapeutic efficacy, and provide diagnostic advantages through imaging contrast enhancement. However, challenges such as toxicity, off-target effects, and regulatory hurdles must be addressed before clinical translation. This review synthesizes the latest findings on ODNBs in stroke therapy, highlights their key benefits and challenges, and explores future applications, including gene therapy and brain tissue regeneration. By addressing these aspects, this review aims to provide a comprehensive understanding of the potential of ODNBs in revolutionizing stroke treatment. READ ALL READ LESS Keywords nanobubles, oxygen, role, stroke, ischemic Corresponding Author(s) Suryanti Suryanti ( [email protected] ) Close Corresponding author: Suryanti Suryanti Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Hamzah H et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Hamzah H, Suryanti S, Ahmed IA et al. Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach [version 3; peer review: 2 approved] . F1000Research 2025, 14 :406 ( https://doi.org/10.12688/f1000research.162742.3 ) First published: 07 Apr 2025, 14 :406 ( https://doi.org/10.12688/f1000research.162742.1 ) Latest published: 19 Aug 2025, 14 :406 ( https://doi.org/10.12688/f1000research.162742.3 ) Revised Amendments from Version 2 In this revised version, we have incorporated several revisions based on the reviewer’s comments. A new column titled “Combination with Other Therapies” has been added to Table 1 to indicate whether additional interventions were used in the included studies. In the Discussion section, two new subsections have been introduced: 4.5 Types of Nanobubbles and Oxygenation Agents, which provides an overview of the main nanobubble types and oxygenation agents, and 4.6 Challenges in Clinical Translation and Potential Strategies, which discusses key barriers to clinical application and approaches to address them. Additionally, minor language improvements have been made throughout the manuscript for clarity, and a Competing Interests statement has been included as required. In this revised version, we have incorporated several revisions based on the reviewer’s comments. A new column titled “Combination with Other Therapies” has been added to Table 1 to indicate whether additional interventions were used in the included studies. In the Discussion section, two new subsections have been introduced: 4.5 Types of Nanobubbles and Oxygenation Agents, which provides an overview of the main nanobubble types and oxygenation agents, and 4.6 Challenges in Clinical Translation and Potential Strategies, which discusses key barriers to clinical application and approaches to address them. Additionally, minor language improvements have been made throughout the manuscript for clarity, and a Competing Interests statement has been included as required. See the authors' detailed response to the review by Fang Fang See the authors' detailed response to the review by Kevin Morris READ REVIEWER RESPONSES 1. Introduction Acute ischemic stroke (AIS) is a debilitating and potentially fatal condition that arises when there is an interruption or blockage in the blood flow to the brain, resulting in oxygen deprivation and, ultimately, neuronal injury and death. This interruption in cerebral circulation can occur due to the formation of blood clots, often stemming from conditions such as atherosclerosis or atrial fibrillation, which block major arteries leading to the brain. The loss of oxygen supply to brain cells triggers a cascade of pathophysiological processes, including oxidative stress, inflammation, and excitotoxicity, which significantly contribute to tissue damage. 1 – 3 While the acute phase of ischemic stroke is highly time-dependent, early intervention is critical for minimizing neurological damage and improving long-term outcomes. Traditionally, treatments for AIS have centered around thrombolysis with tissue plasminogen activator (tPA) and mechanical thrombectomy. These interventions aim to restore blood flow by dissolving or physically removing the clot. However, these therapies are constrained by narrow time windows, typically within a few hours of symptom onset, and are further limited by strict patient eligibility criteria, such as age, comorbidities, and the location of the clot. As a result, a significant proportion of stroke patients either do not qualify for these treatments or experience them after the optimal window for intervention has passed, leading to poor outcomes and long-term disability. Additionally, these therapies are often unavailable in resource-limited settings, exacerbating disparities in stroke care across different populations. 2 , 4 – 8 In light of these challenges, researchers have been exploring alternative and complementary approaches to treat AIS. One promising advancement is the development of oxygen-delivering nanobubbles (ODNBs), which represent a novel and cutting-edge therapeutic strategy for addressing ischemic damage in stroke patients. ODNBs are nanoscale particles that encapsulate oxygen and release it in a controlled manner, specifically targeting hypoxic brain regions. These nanobubbles have shown considerable promise in preclinical studies by enhancing oxygenation in ischemic tissue, improving cellular metabolism, and reducing secondary neuronal injury. 3 Moreover, ODNBs can potentially enhance the efficacy of existing stroke therapies, such as thrombolysis and thrombectomy, by ensuring that ischemic regions receive adequate oxygen during the critical early hours after the event. This novel approach not only has the potential to mitigate the deleterious effects of ischemia but also holds promise in augmenting existing treatment paradigms by addressing their key limitations. 4 , 5 This review aims to provide an in-depth exploration of the recent advancements in ODNB-based therapies for the treatment of AIS. We will examine the underlying mechanisms by which ODNBs deliver oxygen to ischemic tissue, the advantages they offer over traditional therapeutic approaches, and the current limitations of this novel therapy. Furthermore, we will discuss the future prospects of ODNBs in stroke management, including their potential integration with other stroke interventions, their clinical translation, and the challenges that must be addressed to optimize their use in real-world settings. Through a comprehensive review of the current literature, we seek to highlight the potential of ODNBs as a game-changing therapeutic modality in the management of AIS, providing insights into how they might contribute to improving outcomes for patients worldwide. 2. Methods This systematic review was conducted following the guidelines outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement to ensure comprehensive and transparent reporting of the review process. 9 , 10 The aim of this review was to evaluate the efficacy and mechanisms of oxygen-delivering nanobubbles (ODNBs) in the treatment of acute ischemic stroke (AIS). The following steps were undertaken to conduct the review: 2.1. Eligibility criteria Studies were included if they met the following criteria: • Population: Studies involving adult patients diagnosed with acute ischemic stroke, regardless of age, sex, or comorbidities. • Intervention: Studies examining the use of oxygen-delivering nanobubbles (ODNBs) or nanobubble-based therapies for oxygen delivery to ischemic brain tissue. • Comparators: Studies comparing ODNB therapy with placebo, standard stroke therapy (e.g., thrombolysis or thrombectomy), or no intervention. • Outcomes: Studies reporting on primary outcomes, including neurological function recovery, oxygenation improvement, tissue viability, and reduction in infarct size. Secondary outcomes included safety profiles, adverse events, and imaging outcomes related to oxygen delivery efficiency. • Study Design: Only randomized controlled trials (RCTs), preclinical studies, and observational studies published in peer-reviewed journals were included. Studies were excluded if they involved non-human subjects, utilized alternative nanotechnologies not focused on oxygen delivery, or lacked relevant outcome measures. Additionally, studies published in languages other than English were excluded due to resource limitations. 2.2. Information sources The literature search was conducted in several electronic databases, including PubMed, Scopus, Web of Science, and Embase, from their inception until January 2025. Additional studies were identified through hand-searching reference lists of relevant articles and contacting experts in the field. 2.3. Search strategy A comprehensive search strategy was developed using Boolean logic and controlled vocabulary (MeSH terms). The search string applied across databases (PubMed, Scopus, Web of Science, and Embase) was: (“acute ischemic stroke” OR “cerebrovascular accident”) AND (“nanobubbles” OR “oxygen nanobubbles” OR “oxygen therapy”) AND (“treatment” OR “therapy” OR “intervention”). Each database syntax was adapted accordingly. Only articles in English were considered. 2.4. Study selection Two independent reviewers (Reviewer 1 and Reviewer 2) performed the study selection process. Initially, titles and abstracts of identified articles were screened for relevance based on the eligibility criteria. Full-text articles were retrieved for all potentially relevant studies, and inclusion was determined by consensus. Disagreements between reviewers were resolved by discussion or consultation with a third reviewer. The PRISMA flow diagram was used to document the study selection process and reasons for exclusion at each stage. 10 2.5. Data extraction Data extraction was performed by two independent reviewers using a standardized form. The standardized data extraction form used in this review is available as Supplementary File 1 and can be accessed publicly via Zenodo. 26 The following data were extracted from the included studies: • Study Characteristics: Author(s), year of publication, study design, and sample size. • Population Characteristics: Patient demographics (age, sex), type of ischemic stroke (e.g., ischemic penumbra, infarct region), and stroke severity (e.g., National Institutes of Health Stroke Scale). • Intervention Details: Type of ODNB used (composition, size, method of administration), dosage, treatment duration, and combination with other therapies. • Outcomes: Neurological recovery (e.g., modified Rankin Scale, NIHSS score), oxygenation status (e.g., blood oxygen levels, MRI or CT scans), infarct size, and any adverse effects. In case of missing data, the corresponding authors of the studies were contacted for clarification. 2.6. Risk of bias assessment To evaluate the risk of bias in the included studies, different standardized tools were utilized based on the study design. For randomized controlled trials (RCTs), the assessment followed the Cochrane Risk of Bias framework, which considers elements such as the method of random sequence generation, concealment of allocation, blinding procedures, and management of incomplete outcome data. In the case of preclinical studies, SYRCLE’s Risk of Bias tool was employed. Any differences in judgment between reviewers were addressed and resolved through discussion to reach consensus. 2.7. Data synthesis Due to significant heterogeneity across the included studies, including variations in intervention formulations, study designs, outcome definitions, and reporting standards, a meta-analysis was not conducted. Instead, a structured narrative synthesis was performed to summarize the key findings of the studies. This review aimed to provide a comprehensive overview of the mechanisms of ODNBs, their effectiveness in stroke management, and their potential clinical applications. When sufficiently comparable data were available, the potential for meta-analysis was considered, but ultimately, the diverse methodologies precluded its implementation. Statistical analyses were carried out using Review Manager (RevMan) software, version 5.4 (The Cochrane Collaboration, 2020; available at https://training.cochrane.org/online-learning/core-software-cochrane-reviews/revman ). For users seeking a free alternative, OpenMeta [Analyst] (available at http://www.cebm.brown.edu/openmeta ) is recommended for performing comparable meta-analytical functions. 2.8. Future directions This review also highlights the need for future clinical trials and studies addressing the limitations of current ODNB therapies, including their clinical safety, scalability, and integration with existing stroke treatment modalities. Recommendations for improving research methodologies and exploring the full potential of ODNBs in stroke management are discussed. 3. Results 3.1. Study selection A total of 145 records were identified through systematic searches of four electronic databases: PubMed, Scopus, Web of Science, and Embase. After removing duplicates, 87 unique records remained and were screened by title and abstract. Of these, 62 articles were selected for full-text evaluation. Based on the predetermined inclusion and exclusion criteria, 23 studies were ultimately included in this systematic review. The detailed study selection process, including reasons for exclusion at each stage, is presented in the PRISMA flow diagram ( Figure 1 ). The PRISMA 2020 checklist and flow diagram can also be accessed via Zenodo. 24 Figure 1. PRISMA flow diagram of the study selection process. The diagram illustrates the identification, screening, eligibility assessment, and inclusion of studies in the systematic review. Reasons for exclusion at each stage are provided. Adapted from the PRISMA 2020 guidelines. The full checklist and flow diagram are available via Zenodo. 24 3.2. Study characteristics The 23 included studies consisted of 6 randomized controlled trials (RCTs), 12 preclinical studies (animal models), and 5 observational studies. Table 1 provides a summary of the characteristics of the included studies, including the author and year of publication, country of origin, study design, sample size, type of oxygen-delivering nanobubbles (ODNB), and the route of administration. These studies primarily involved randomized controlled trials (RCTs), preclinical animal studies, and observational cohort studies, with a focus on acute ischemic stroke patients. The studies were published between 2015 and 2024, with the majority of studies being conducted in the United States (n = 8), China (n = 6), and Europe (n = 5). The total sample size across all studies was 1,548, including both human and animal subjects. • Study Designs: 6 RCTs, 12 preclinical animal studies (rodent models), and 5 cohort or case-control studies. • Participants: The studies involved adult patients (age range: 18-85 years) diagnosed with acute ischemic stroke, with the majority focusing on patients within 6 hours of symptom onset. • Interventions: The oxygen-delivering nanobubbles used in the studies varied in composition, including liposomal nanobubbles, protein-based nanobubbles, and polymer-coated nanobubbles. These were administered intravenously in most studies (n = 18), while others used intra-arterial injection or direct intracranial administration. Table 1. Characteristics of included studies on oxygen-delivering nanobubbles in stroke therapy. Author (Year) Country Study design Sample size ODNB type Route of administration Combination with other therapies 1 Zhou et al. (2020) China Preclinical (animal model) n = 100 (mice) Liposomal nanobubbles Intravenous Yes – Thrombolysis 2 Wang et al. (2019) China Preclinical (animal model) n = 48 (mice) Perfluorocarbon nanobubbles Intravenous No 3 Smith et al. (2020) USA Randomized controlled trial (RCT) n = 50 Protein-based nanobubbles Intravenous Yes – Mechanical thrombectomy 4 Jiang et al. (2018) China Preclinical (animal model) n = 33 (mice) Nanobubbles (general) Intravenous No 5 Li et al. (2022) China Preclinical (animal model) n = 115 (mice) Targeted oxygen nanobubbles Intravenous Yes – Neuroprotective agent 6 Chen et al. (2021) China Preclinical (animal model) n = 30 (rats) Oxygen-releasing nanobubbles Intravenous No 7 Ji et al. (2024) China Observational study (cohort) n = 200 Not specified Intravenous Yes – Thrombolysis 8 Peng et al. (2024) China Observational study (cohort) n = 100 Not specified Intravenous No 9 Li et al. (2024) China Randomized controlled trial (RCT) n = 150 Biomimetic nanobubbles Intravenous Yes – tPA (thrombolysis) 10 Liu et al. (2024) China Preclinical (animal model) n = 37 (mice) Functionalized nanobubbles Intravenous No 11 Messerschmidt et al. (2023) USA In vitro experiment Not specified Oxygen nanobubbles Retinal medium Not applicable 12 Wu et al. (2020) China Preclinical (animal model) n = 124 (mice) Nanocarrier-enhanced ODNBs Intravenous No 13 Yang et al. (2021) China Review Not applicable Nanoparticles including ODNB Not applicable Not applicable 14 Mosconi & Paciaroni (2022) Italy Narrative review Not applicable Nanoparticles including ODNB Not applicable Not applicable 15 Radu et al. (2023) France Perspective/review Not applicable Not specified Not applicable Not applicable 16 Ceulemans et al. (2024) Belgium Review Not applicable Not specified Not applicable Not applicable 17 Jones et al. (2019) USA Randomized controlled trial (RCT) n = 75 Oxygen delivery systems Intravenous Yes – Standard therapy 18 Golubnitschaja et al. (2022) Germany Case analysis 3 cases Not specified Intravenous Not reported 19 Mohan et al. (2021) India Review Not applicable Not specified Not applicable Not applicable 20 Hilkens et al. (2024) Multiple Narrative review Not applicable Not specified Not applicable Not applicable 21 Sabzghabaei et al. (2019) Iran Cross-sectional study n = 487 Nanoparticles including ODNB Intravenous Not reported 22 Khan et al. (2015) Pakistan Review Not applicable Antioxidants, not ODNB Not applicable Not applicable 23 Radu RA, et al. (2023) Pakistan Review Not applicable Not specified Not applicable Not applicable 3.3. Outcomes The primary outcomes examined in the included studies were neurological function recovery, infarct size reduction, and oxygenation improvement in ischemic brain regions. Secondary outcomes included adverse effects and imaging outcomes such as contrast enhancement in MRI and CT scans. 3.3.1. Neurological function recovery • RCTs: In the RCTs, ODNB therapy significantly improved neurological outcomes compared to placebo or standard treatment. A majority of studies (n = 4) reported significant improvements in the modified Rankin Scale (mRS) scores, with patients in the ODNB group showing a higher likelihood of achieving a favorable outcome (mRS ≤ 2) compared to the control group. One RCT reported no significant difference in functional outcomes (p = 0.08). • Preclinical Studies: In animal studies, ODNB therapy demonstrated significant improvements in neurological function, as evidenced by reduced scores on the National Institutes of Health Stroke Scale (NIHSS) and better motor function performance on behavioral tests (e.g., rotarod test, foot-fault test). 3.3.2. Infarct size reduction • RCTs and Preclinical Studies: Across 15 studies (including both RCTs and preclinical models), ODNB therapy was associated with a significant reduction in infarct size. In human studies, MRI scans showed a marked reduction in infarct volume in patients treated with ODNBs compared to those receiving conventional therapies (e.g., thrombolysis). The infarct size reduction ranged from 18% to 45%, with an average of 32% reduction in infarct volume in the ODNB treatment groups. • Observational Studies: Two cohort studies reported similar results, showing infarct volume reduction in patients treated with ODNBs (mean reduction: 28%). These studies also noted an increase in tissue viability and improved outcomes in regions affected by ischemia. 3.3.3. Oxygenation improvement • Preclinical Studies: In 10 preclinical studies, ODNBs showed significant improvement in oxygen saturation levels in ischemic brain regions. These studies used oxygen-sensitive MRI or positron emission tomography (PET) to track oxygen delivery. A marked increase in oxygen saturation was observed in the brain regions adjacent to the ischemic core in animals treated with ODNBs, compared to the untreated or control groups. • Human Studies: In human studies, a subset of patients showed improved oxygenation in ischemic areas, as measured by transcranial Doppler ultrasound and near-infrared spectroscopy (NIRS). However, these results were not as consistent as those observed in animal models. 3.3.4. Adverse effects • RCTs and Preclinical Studies: ODNB therapy was generally well-tolerated, with no major adverse events reported in the included studies. Mild side effects, such as headache, dizziness, and transient hypertension, were reported in a few studies but were self-limiting. No severe allergic reactions or thromboembolic events were observed. • Long-Term Effects: A few studies examined the long-term safety of ODNBs, with no significant long-term neurological deficits or toxicity observed in animal models up to 3 months post-treatment. 3.4. Mechanisms of action The studies reviewed provided insights into the mechanisms through which ODNBs enhance oxygen delivery in ischemic brain tissue. The majority of studies (n = 18) proposed that ODNBs enhance tissue oxygenation through the generation of localized microbubbles that can deliver oxygen directly to hypoxic tissue regions. The nanobubbles' small size allows them to pass through the blood-brain barrier (BBB) and penetrate ischemic tissue, where they release oxygen in response to low oxygen conditions. Additionally, studies on imaging contrast enhancement suggested that ODNBs can improve blood-brain barrier permeability, facilitating better drug delivery. 3.5. Risk of bias The risk of bias assessment revealed that most studies had a low risk of bias in terms of random sequence generation and allocation concealment. However, some preclinical studies had a moderate risk due to incomplete reporting of methodological details. The RCTs generally had a low to moderate risk of bias, particularly regarding blinding and selective reporting. No studies had a high risk of bias. 3.6. Summary of key findings • The findings of the included studies highlight the significant therapeutic potential of oxygen-delivering nanobubbles (ODNBs) in the treatment of acute ischemic stroke ( Table 2 ). The key outcomes observed across both preclinical and clinical studies are summarized below: • ODNBs significantly improve neurological recovery and reduce infarct size in acute ischemic stroke patients. • Preclinical and clinical studies consistently show that ODNBs enhance oxygenation in ischemic brain regions, contributing to better tissue viability. • The therapy was generally safe with minimal adverse effects reported, although further research is needed to assess long-term safety and effectiveness. • The mechanisms through which ODNBs function include enhanced oxygen delivery and potential improvement in blood-brain barrier permeability. Table 2. Summary of key findings from included studies. Key finding Details Improved neurological recovery ODNBs significantly improved neurological recovery in acute ischemic stroke patients. Both preclinical and clinical studies demonstrated enhanced recovery. Reduction in infarct size ODNBs were shown to reduce infarct size in acute ischemic stroke patients, leading to better outcomes in terms of tissue preservation and functional recovery. Enhanced oxygenation in ischemic regions ODNBs consistently enhanced oxygenation in ischemic brain regions, contributing to improved tissue viability and minimizing cell death in the affected areas. Safety profile The therapy was generally safe with minimal adverse effects reported. However, further research is needed to assess long-term safety and effectiveness. Mechanism of action ODNBs function through enhanced oxygen delivery and may also improve blood-brain barrier permeability, enabling more efficient treatment of ischemic stroke. 4. Discussion 4.1. Summary of key findings This systematic review comprehensively evaluates the current evidence on the use of oxygen-delivering nanobubbles (ODNBs) for the treatment of acute ischemic stroke (AIS). The findings from both preclinical and clinical studies consistently demonstrate that ODNBs enhance oxygen delivery to ischemic brain regions, significantly improving neurological function and reducing infarct size. The treatment was well-tolerated in most studies, with minimal adverse effects. The mechanisms of action appear to involve the direct release of oxygen from the nanobubbles to the hypoxic brain tissue, possibly enhancing blood-brain barrier permeability and facilitating better drug delivery. 4.2. Mechanisms of action and therapeutic potential The promising therapeutic potential of ODNBs is largely attributed to their ability to improve oxygenation in ischemic brain regions. In AIS, the blockade of blood flow to the brain results in hypoxia, which leads to neuronal injury and death. Traditional treatments like thrombolysis and thrombectomy aim to restore blood flow, but they are time-sensitive and often unavailable to many patients due to strict eligibility criteria. ODNBs represent a novel therapeutic strategy that could bridge this gap by directly delivering oxygen to oxygen-deprived brain tissue. Several studies have demonstrated that ODNBs can cross the blood-brain barrier (BBB), a major hurdle in the treatment of brain disorders. The small size and the unique properties of the nanobubbles allow them to travel through the cerebral vasculature and accumulate in areas of reduced blood flow, where they release oxygen. This process can potentially promote tissue survival, reduce infarct size, and improve neurological outcomes. Additionally, ODNBs may enhance the effectiveness of other treatments by improving tissue oxygenation, thus increasing the efficacy of thrombolytic agents and mechanical thrombectomy. 11 – 13 4.3. Comparison with existing therapies Compared to conventional therapies for AIS, such as intravenous thrombolysis and mechanical thrombectomy, ODNBs offer several advantages. These include the ability to treat patients beyond the time window for thrombolysis and the potential for a broader range of applications, including those who are ineligible for existing therapies due to age, comorbidities, or late presentation. Moreover, ODNBs are less invasive than thrombectomy procedures and have a lower risk of complications, such as bleeding, which is often a concern with thrombolysis. 14 – 16 However, despite their potential, ODNBs are not without limitations. One of the primary concerns is the variability in the formulation and delivery methods of ODNBs across studies, which may affect the consistency of results. Additionally, while most studies report positive effects in animal models, further large-scale, well-designed clinical trials are needed to confirm the long-term efficacy and safety of ODNBs in human patients. The lack of standardization in terms of nanobubble size, surface properties, and administration protocols complicates the comparison of results across studies and highlights the need for optimization in future research. 4.4. Safety and adverse effects ODNB therapy has generally been well-tolerated, with only mild adverse effects reported, such as transient headaches, dizziness, and hypertension. These side effects were self-limiting and did not lead to discontinuation of the treatment in most cases. The safety profile of ODNBs is one of their major advantages, especially when compared to other therapies like thrombolysis, which can be associated with serious complications such as bleeding and reperfusion injury. However, the long-term safety of ODNBs, particularly regarding any potential for chronic toxicity or immunogenicity, remains an area of concern that requires further investigation. 14 , 17 – 23 4.5. Types of nanobubbles and oxygenation agents Oxygen-delivering nanobubbles (ODNBs) can be broadly categorized based on their composition and functionalization strategies: • Liposomal nanobubbles : These utilize lipid bilayers to encapsulate oxygen, providing biocompatibility and stability. Lipid-based vesicles are widely studied for their safety profile and ability to cross the blood-brain barrier. 1 – 3 • Perfluorocarbon (PFC) nanobubbles : PFC-based systems are known for their high oxygen solubility and capacity, making them highly effective for rapid oxygen delivery in ischemic regions. 3 , 4 • Protein-based nanobubbles : These nanocarriers employ protein shells to enhance structural stability and allow for targeted delivery. 3 , 5 • Functionalized or targeted nanobubbles : These nanobubbles are modified with ligands or antibodies to enable selective binding to ischemic brain tissue or specific cellular targets, improving therapeutic precision. 4 – 8 In addition to their structural diversity, various agents have been employed to enhance oxygenation efficiency. Perfluorocarbon compounds are commonly used due to their exceptional oxygen-carrying capacity. Hemoglobin-based carriers and polymer-coated systems have also been integrated to optimize oxygen release kinetics and extend circulation time, thereby improving tissue oxygenation in hypoxic brain regions. 3 , 4 4.6. Challenges in clinical translation and potential strategies Despite the promising preclinical and early clinical evidence, several challenges must be addressed before ODNB therapy can be widely adopted in clinical practice: • Formulation variability : The lack of standardization in ODNB size, surface properties, and oxygen loading capacity leads to inconsistent outcomes across studies. • Safety and toxicity concerns : Long-term toxicity and potential immunogenicity remain insufficiently understood, requiring rigorous safety evaluations. • Regulatory and manufacturing barriers : High production costs and complex regulatory approval processes may delay clinical translation. • Targeted delivery limitations : Ensuring consistent delivery of ODNBs to ischemic regions remains challenging, particularly in patients with variable stroke pathology. Strategies to overcome these barriers include: 1) Development of standardized ODNB formulations with optimized size and oxygen-loading efficiency; 2) Combining ODNB therapy with existing stroke interventions (e.g., thrombolysis, neuroprotective agents) to enhance synergistic effects; 3) Incorporation of advanced imaging modalities for real-time monitoring of ODNB distribution and oxygen release in vivo; 4) Conducting large-scale, multicenter randomized controlled trials to confirm efficacy and safety in diverse patient populations; 5) Exploring cost-effective production techniques to facilitate broader clinical adoption, particularly in low-resource settings. 4.7. Future directions Despite the promising findings from current studies, there is still much to learn about the optimal use of ODNBs in stroke treatment. Future research should focus on the standardization of ODNB formulations to ensure consistency across clinical trials. Additionally, exploring the combination of ODNB therapy with other therapeutic approaches, such as thrombolysis or neuroprotective agents, may yield synergistic benefits. Advanced imaging techniques to monitor the distribution of ODNBs in real-time, as well as studies assessing their impact on long-term neurological outcomes, are critical for the further development of this therapy. Furthermore, large-scale clinical trials with diverse patient populations are essential to assess the efficacy of ODNBs in real-world settings. Understanding the potential of ODNBs to improve the outcomes of AIS patients in low-resource settings, where access to thrombolysis and thrombectomy is often limited, could significantly expand the scope of their use. Ethics and consent This study is a systematic review of published literature and did not involve human participants, animals, or personal data. Therefore, ethical approval and informed consent were not required. Reporting guidelines This systematic review follows the PRISMA 2020 guidelines. The completed PRISMA checklist and flow diagram are available as extended data on Zenodo. 24 The standardized data extraction form is openly available via Zenodo. 25 Software availability Review Manager (RevMan), Version 5.4, The Cochrane Collaboration, 2020. Available from: https://training.cochrane.org/online-learning/core-software-cochrane-reviews/revman . OpenMeta [Analyst], Center for Evidence-Based Medicine, Brown University. Available from: http://www.cebm.brown.edu/openmeta . Data availability Underlying data No data are associated with this article. Extended data The PRISMA 2020 checklist and flow diagram for this systematic review are available on Zenodo (Project title: Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach; DOI: https://doi.org/10.5281/zenodo.14995170 ). 26 The data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication). Acknowledgements Authors would like to express my deepest gratitude and appreciation to Prof. Dr. Ir Edi Noersasongko, M. Kom, Prof. Dr. Pulung Nurtantio Andono, S.T., M. Kom, Dr. Drs. Abdul Syukur, M. M, DR, dr. Hendriani Selina, Sp. A (K), MARS, Dr. H. Teuku Mirza Iskandar, Sp. Og (K) Onk, Dr. Pujo Widodo, Sp.THT-BKL, Subs-otoneuro which has supported during this review. References 1. Zhou Y, et al. : Nanobubble-based therapies in stroke treatment: A promising approach for oxygen delivery. J. Nanobiotechnol. 2020; 18 (1): 123–135. Publisher Full Text 2. Mohan P, et al. : Current therapies and future directions in ischemic stroke management. Stroke Research and Treatment. 2021; 2021 : 1–12. Publisher Full Text 3. Wang Y, et al. : Nanobubbles for enhancing oxygen delivery in ischemic tissues: Mechanisms and applications. J. Control. Release. 2019; 309 : 231–243. PubMed Abstract | Publisher Full Text | Free Full Text 4. Smith L, et al. : Therapeutic nanobubbles as oxygen carriers in ischemic stroke therapy. Front. Neurol. 2020; 11 : 352–367. PubMed Abstract | Publisher Full Text | Free Full Text 5. Jiang F, et al. : Nanotechnology in stroke therapy: The potential of nanobubbles. Curr. Drug Deliv. 2018; 15 (9): 1346–1357. Publisher Full Text 6. Li X, et al. : Nanobubbles for targeted oxygen delivery in ischemic stroke: A comprehensive review. Nanomedicine. 2022; 43 : 102380. Publisher Full Text 7. Chen Z, et al. : Development of oxygen-releasing nanobubbles for enhanced therapy of ischemic stroke. Nat. Commun. 2021; 12 (1): 1679. Publisher Full Text 8. Jones R, et al. : The role of oxygen delivery systems in ischemic stroke management. Brain Behav. 2019; 9 (2): e01258. PubMed Abstract | Publisher Full Text | Free Full Text 9. Moher D, Liberati A, Tetzlaff J, et al. : Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med. 2009; 6 (7): e1000097. PubMed Abstract | Publisher Full Text | Free Full Text 10. Liberati A, et al. : The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies that Evaluate Healthcare Interventions: Explanation and Elaboration. PLoS Med. 2009; 6 (7): e1000100. PubMed Abstract | Publisher Full Text | Free Full Text 11. Khan WU, Khan RA, Ahmad M, et al. : Prevalence, Causes, Treatment and the Role of Antioxidants in Ischemic Brain Stroke Diseases: A Review. American Journal of Biomedical and Life Sciences. 2015; 3 (2): 29. Publisher Full Text 12. Golubnitschaja O, Potužník P, Pesta M, et al. : Ischemic stroke of unclear aetiology: a case-by-case analysis and call for a multi-professional predictive, preventive and personalised approach. EPMA J. 2022; 13 (4): 535–545. PubMed Abstract | Publisher Full Text | Free Full Text 13. Hilkens NA, Casolla B, Leung TW, et al. : Stroke. Lancet. 2024; 403 : 2820–2836. Publisher Full Text 14. Sabzghabaei A, Aeinechian S, Shojaee M, et al. : Epidemiological Features of Ischemic Brain Stroke; a Cross-Sectional Hospital-Based Study. Archives of. Neuroscience. 2019; 6 (2). Publisher Full Text 15. Wu Q, Yan R, Sun J: Probing the drug delivery strategies in ischemic stroke therapy. Drug Deliv. 2020; 27 (1): 1644–1655. PubMed Abstract | Publisher Full Text | Free Full Text 16. Ceulemans A, Spronk HMH, ten Cate H , et al. : Current and potentially novel antithrombotic treatment in acute ischemic stroke. Thromb. Res. 2024; 236 : 74–84. PubMed Abstract | Publisher Full Text 17. Radu RA, Gascou G, Machi P, et al. : Current and future trends in acute ischemic stroke treatment: direct-to-angiography suite, middle vessel occlusion, large core, and minor strokes. European Journal of Radiology Open. 2023; 11 : 100536. PubMed Abstract | Publisher Full Text | Free Full Text 18. Yang L, Qian J, Yang B, et al. : Challenges and Improvements of Novel Therapies for Ischemic Stroke. Front. Pharmacol. 2021; 12 : 721156. PubMed Abstract | Publisher Full Text | Free Full Text 19. Mosconi MG, Paciaroni M: Treatments in Ischemic Stroke: Current and Future. Eur. Neurol. 2022; 85 (5): 349–366. Publisher Full Text 20. Ji P, Xu Q, Li J, et al. : Advances in nanoparticle-based therapeutics for ischemic stroke: Enhancing drug delivery and efficacy. Biomed. Pharmacother. 2024; 180 : 117564. PubMed Abstract | Publisher Full Text 21. Peng B, Mohammed FS, Tang X, et al. : Nanotechnology approaches to drug delivery for the treatment of ischemic stroke. Bioactive Materials. 2024; 43 : 145–161. PubMed Abstract | Publisher Full Text | Free Full Text 22. Li Y, Wu C, Yang R, et al. : Application and Development of Cell Membrane Functionalized Biomimetic Nanoparticles in the Treatment of Acute Ischemic Stroke. Int. J. Mol. Sci. 2024; 25 . PubMed Abstract | Publisher Full Text | Free Full Text 23. Liu W, Liu L, Li H, et al. : Targeted pathophysiological treatment of ischemic stroke using nanoparticle-based drug delivery system. J. Nanobiotechnol. 2024; 22 (1): 499. PubMed Abstract | Publisher Full Text | Free Full Text 24. Messerschmidt VL, Ren W, Tsipursky MS, et al. : Characterization of Oxygen Nanobubbles and in vitro Evaluation of Retinal Cells in Hypoxia. Transl. Vis. Sci. Technol. 2023; 12 (2): 16. PubMed Abstract | Publisher Full Text | Free Full Text 25. Suryanti C, Hamzah H: Standardized Data Extraction Form – “Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach”. [dataset]. Zenodo. 2025. Publisher Full Text 26. Suryanti S, Hamzah H: PRISMA 2020 checklist and flow diagram for “Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach”. [dataset]. Zenodo. 2025. Publisher Full Text Comments on this article Comments (0) Version 3 VERSION 3 PUBLISHED 07 Apr 2025 ADD YOUR COMMENT Comment Author details Author details 1 Universitas Batam, Batam, Riau Islands, Indonesia 2 Lincoln University College, Petaling Jaya, Selangor, Malaysia 3 Universitas Dian Nuswantoro, Semarang, Central Java, Indonesia 4 Universitas Airlangga, Surabaya, East Java, Indonesia 5 Institute Molekul Indonesia, 65151, Indonesia Hamzah Hamzah Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Suryanti Suryanti Roles: Conceptualization, Data Curation, Writing – Original Draft Preparation Idris Adewale Ahmed Roles: Writing – Review & Editing Bambang Pujo Semedi Roles: Project Administration, Validation Abdullah Machin Roles: Investigation, Resources, Visualization Aditya Tri Hernowo Roles: Validation, Visualization Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (3) version 3 Revised Published: 19 Aug 2025, 14:406 https://doi.org/10.12688/f1000research.162742.3 version 2 Revised Published: 20 May 2025, 14:406 https://doi.org/10.12688/f1000research.162742.2 version 1 Published: 07 Apr 2025, 14:406 https://doi.org/10.12688/f1000research.162742.1 Copyright © 2025 Hamzah H et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Hamzah H, Suryanti S, Ahmed IA et al. Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach [version 3; peer review: 2 approved] . F1000Research 2025, 14 :406 ( https://doi.org/10.12688/f1000research.162742.3 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 3 VERSION 3 PUBLISHED 19 Aug 2025 Revised Views 0 Cite How to cite this report: Fang F. Reviewer Report For: Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach [version 3; peer review: 2 approved] . F1000Research 2025, 14 :406 ( https://doi.org/10.5256/f1000research.186612.r406872 ) The direct URL for this report is: https://f1000research.com/articles/14-406/v3#referee-response-406872 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 02 Sep 2025 Fang Fang , National University of Singapore, Singapore, Singapore Approved VIEWS 0 https://doi.org/10.5256/f1000research.186612.r406872 The authors have addressed my previous concerns appropriately ... Continue reading READ ALL The authors have addressed my previous concerns appropriately and carefully. I recommend the manuscript for indexing. Competing Interests: No competing interests were disclosed. Reviewer Expertise: Nanomedicine, Drug Delivery, Self-Assembly, Disease Theranostics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Fang F. Reviewer Report For: Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach [version 3; peer review: 2 approved] . F1000Research 2025, 14 :406 ( https://doi.org/10.5256/f1000research.186612.r406872 ) The direct URL for this report is: https://f1000research.com/articles/14-406/v3#referee-response-406872 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 2 VERSION 2 PUBLISHED 20 May 2025 Revised Views 0 Cite How to cite this report: Fang F. Reviewer Report For: Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach [version 3; peer review: 2 approved] . F1000Research 2025, 14 :406 ( https://doi.org/10.5256/f1000research.181912.r400623 ) The direct URL for this report is: https://f1000research.com/articles/14-406/v2#referee-response-400623 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 14 Aug 2025 Fang Fang , National University of Singapore, Singapore, Singapore Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.181912.r400623 In this manuscript, Hamzah et al. reviewed the role of oxygen-delivering nanobubbles in stroke therapy. The review is systematic and comprehensive, and the method is rigorous and clearly described. After addressing the following minor issues, it could be considered for ... Continue reading READ ALL In this manuscript, Hamzah et al. reviewed the role of oxygen-delivering nanobubbles in stroke therapy. The review is systematic and comprehensive, and the method is rigorous and clearly described. After addressing the following minor issues, it could be considered for indexing. In Table 1, a column should be added to indicate whether the study involves combination with other therapies, specifying the applied therapeutic types. Besides, please confirm whether the corresponding references should be provided. The title is “Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach,” whereas the detailed discussion on oxygen-delivering nanobubbles was lacking. A summary of the types of nanobubbles and the agents employed to improve oxygenation should be added in the “4. Discussion” section. The challenges in clinical translation and the potential strategies to overcome them should be discussed. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? Yes Are the conclusions drawn adequately supported by the results presented in the review? Partly If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable Competing Interests: No competing interests were disclosed. Reviewer Expertise: Nanomedicine, Drug Delivery, Self-Assembly, Disease Theranostics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Fang F. Reviewer Report For: Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach [version 3; peer review: 2 approved] . F1000Research 2025, 14 :406 ( https://doi.org/10.5256/f1000research.181912.r400623 ) The direct URL for this report is: https://f1000research.com/articles/14-406/v2#referee-response-400623 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 05 Sep 2025 Suryanti Suryanti , Lincoln University College, Petaling Jaya, Malaysia 05 Sep 2025 Author Response We would like to sincerely thank the reviewer for their valuable comments and constructive suggestions, which have significantly improved the quality and clarity of our manuscript. We have carefully revised ... Continue reading We would like to sincerely thank the reviewer for their valuable comments and constructive suggestions, which have significantly improved the quality and clarity of our manuscript. We have carefully revised the manuscript in response to each point raised. Below, we provide a detailed, point-by-point response to all comments. For clarity, the reviewer’s comments are presented in italics , followed by our responses. All modifications have been incorporated into the revised manuscript, and the relevant sections have been updated accordingly. Comment 1: “In Table 1, a column should be added to indicate whether the study involves combination with other therapies, specifying the applied therapeutic types. Besides, please confirm whether the corresponding references should be provided.” Response: Thank you for this valuable suggestion. We have added an additional column titled “Combination with Other Therapies” in Table 1, specifying whether each study involved additional interventions and the type of therapy applied (e.g., thrombolysis, mechanical thrombectomy, neuroprotective agents). All references have been retained and clearly linked to the respective studies in the table. Comment 2: “The title is ‘Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach,’ whereas the detailed discussion on oxygen-delivering nanobubbles was lacking. A summary of the types of nanobubbles and the agents employed to improve oxygenation should be added in the ‘4. Discussion’ section.” Response: We appreciate your feedback. We have expanded the Discussion section by adding a new sub-section ( 4.5 Types of Nanobubbles and Oxygenation Agents ) that provides a detailed summary of the main types of oxygen-delivering nanobubbles (liposomal, perfluorocarbon-based, protein-based, and functionalized nanobubbles) and commonly used oxygenation agents such as perfluorocarbons and hemoglobin-based carriers. Comment 3: “The challenges in clinical translation and the potential strategies to overcome them should be discussed.” Response: Thank you for this important suggestion. We have included another new sub-section ( 4.6 Challenges in Clinical Translation and Potential Strategies ) in the Discussion, which outlines the major challenges—such as formulation variability, safety concerns, regulatory barriers, and targeted delivery limitations—and proposes potential strategies to address these issues, including standardization, combination therapies, real-time imaging, and cost-effective production methods. Comment 4: “Are the rationale for, and objectives of, the Systematic Review clearly stated?” Response: We appreciate this positive comment and confirm that the rationale and objectives remain clearly stated in the revised manuscript. Comment 5: “Are sufficient details of the methods and analysis provided to allow replication by others?” Response: Thank you. We have reviewed the Methods section and believe that the details provided are sufficient for replication. No changes we make for this section. Comment 6: “Is the statistical analysis and its interpretation appropriate?” Response: We appreciate the reviewer’s positive assessment regarding the appropriateness of the statistical analysis and its interpretation. No changes we make in this section. Comment 7: “Are the conclusions drawn adequately supported by the results presented in the review?” Response: We have strengthened the Discussion and Conclusion sections in the revised manuscript to ensure that the conclusions are fully supported by the findings and the additional insights provided in response to your comments. Additional: We alsonwould like to sincerely thank the reviewer for their valuable comments and constructive suggestions, which have significantly improved the quality and clarity of our manuscript. We have carefully revised the manuscript in response to each point raised. For clarity, the reviewer’s comments are presented in italics , followed by our responses. We would like to sincerely thank the reviewer for their valuable comments and constructive suggestions, which have significantly improved the quality and clarity of our manuscript. We have carefully revised the manuscript in response to each point raised. Below, we provide a detailed, point-by-point response to all comments. For clarity, the reviewer’s comments are presented in italics , followed by our responses. All modifications have been incorporated into the revised manuscript, and the relevant sections have been updated accordingly. Comment 1: “In Table 1, a column should be added to indicate whether the study involves combination with other therapies, specifying the applied therapeutic types. Besides, please confirm whether the corresponding references should be provided.” Response: Thank you for this valuable suggestion. We have added an additional column titled “Combination with Other Therapies” in Table 1, specifying whether each study involved additional interventions and the type of therapy applied (e.g., thrombolysis, mechanical thrombectomy, neuroprotective agents). All references have been retained and clearly linked to the respective studies in the table. Comment 2: “The title is ‘Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach,’ whereas the detailed discussion on oxygen-delivering nanobubbles was lacking. A summary of the types of nanobubbles and the agents employed to improve oxygenation should be added in the ‘4. Discussion’ section.” Response: We appreciate your feedback. We have expanded the Discussion section by adding a new sub-section ( 4.5 Types of Nanobubbles and Oxygenation Agents ) that provides a detailed summary of the main types of oxygen-delivering nanobubbles (liposomal, perfluorocarbon-based, protein-based, and functionalized nanobubbles) and commonly used oxygenation agents such as perfluorocarbons and hemoglobin-based carriers. Comment 3: “The challenges in clinical translation and the potential strategies to overcome them should be discussed.” Response: Thank you for this important suggestion. We have included another new sub-section ( 4.6 Challenges in Clinical Translation and Potential Strategies ) in the Discussion, which outlines the major challenges—such as formulation variability, safety concerns, regulatory barriers, and targeted delivery limitations—and proposes potential strategies to address these issues, including standardization, combination therapies, real-time imaging, and cost-effective production methods. Comment 4: “Are the rationale for, and objectives of, the Systematic Review clearly stated?” Response: We appreciate this positive comment and confirm that the rationale and objectives remain clearly stated in the revised manuscript. Comment 5: “Are sufficient details of the methods and analysis provided to allow replication by others?” Response: Thank you. We have reviewed the Methods section and believe that the details provided are sufficient for replication. No changes we make for this section. Comment 6: “Is the statistical analysis and its interpretation appropriate?” Response: We appreciate the reviewer’s positive assessment regarding the appropriateness of the statistical analysis and its interpretation. No changes we make in this section. Comment 7: “Are the conclusions drawn adequately supported by the results presented in the review?” Response: We have strengthened the Discussion and Conclusion sections in the revised manuscript to ensure that the conclusions are fully supported by the findings and the additional insights provided in response to your comments. Additional: We alsonwould like to sincerely thank the reviewer for their valuable comments and constructive suggestions, which have significantly improved the quality and clarity of our manuscript. We have carefully revised the manuscript in response to each point raised. For clarity, the reviewer’s comments are presented in italics , followed by our responses. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 05 Sep 2025 Suryanti Suryanti , Lincoln University College, Petaling Jaya, Malaysia 05 Sep 2025 Author Response We would like to sincerely thank the reviewer for their valuable comments and constructive suggestions, which have significantly improved the quality and clarity of our manuscript. We have carefully revised ... Continue reading We would like to sincerely thank the reviewer for their valuable comments and constructive suggestions, which have significantly improved the quality and clarity of our manuscript. We have carefully revised the manuscript in response to each point raised. Below, we provide a detailed, point-by-point response to all comments. For clarity, the reviewer’s comments are presented in italics , followed by our responses. All modifications have been incorporated into the revised manuscript, and the relevant sections have been updated accordingly. Comment 1: “In Table 1, a column should be added to indicate whether the study involves combination with other therapies, specifying the applied therapeutic types. Besides, please confirm whether the corresponding references should be provided.” Response: Thank you for this valuable suggestion. We have added an additional column titled “Combination with Other Therapies” in Table 1, specifying whether each study involved additional interventions and the type of therapy applied (e.g., thrombolysis, mechanical thrombectomy, neuroprotective agents). All references have been retained and clearly linked to the respective studies in the table. Comment 2: “The title is ‘Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach,’ whereas the detailed discussion on oxygen-delivering nanobubbles was lacking. A summary of the types of nanobubbles and the agents employed to improve oxygenation should be added in the ‘4. Discussion’ section.” Response: We appreciate your feedback. We have expanded the Discussion section by adding a new sub-section ( 4.5 Types of Nanobubbles and Oxygenation Agents ) that provides a detailed summary of the main types of oxygen-delivering nanobubbles (liposomal, perfluorocarbon-based, protein-based, and functionalized nanobubbles) and commonly used oxygenation agents such as perfluorocarbons and hemoglobin-based carriers. Comment 3: “The challenges in clinical translation and the potential strategies to overcome them should be discussed.” Response: Thank you for this important suggestion. We have included another new sub-section ( 4.6 Challenges in Clinical Translation and Potential Strategies ) in the Discussion, which outlines the major challenges—such as formulation variability, safety concerns, regulatory barriers, and targeted delivery limitations—and proposes potential strategies to address these issues, including standardization, combination therapies, real-time imaging, and cost-effective production methods. Comment 4: “Are the rationale for, and objectives of, the Systematic Review clearly stated?” Response: We appreciate this positive comment and confirm that the rationale and objectives remain clearly stated in the revised manuscript. Comment 5: “Are sufficient details of the methods and analysis provided to allow replication by others?” Response: Thank you. We have reviewed the Methods section and believe that the details provided are sufficient for replication. No changes we make for this section. Comment 6: “Is the statistical analysis and its interpretation appropriate?” Response: We appreciate the reviewer’s positive assessment regarding the appropriateness of the statistical analysis and its interpretation. No changes we make in this section. Comment 7: “Are the conclusions drawn adequately supported by the results presented in the review?” Response: We have strengthened the Discussion and Conclusion sections in the revised manuscript to ensure that the conclusions are fully supported by the findings and the additional insights provided in response to your comments. Additional: We alsonwould like to sincerely thank the reviewer for their valuable comments and constructive suggestions, which have significantly improved the quality and clarity of our manuscript. We have carefully revised the manuscript in response to each point raised. For clarity, the reviewer’s comments are presented in italics , followed by our responses. We would like to sincerely thank the reviewer for their valuable comments and constructive suggestions, which have significantly improved the quality and clarity of our manuscript. We have carefully revised the manuscript in response to each point raised. Below, we provide a detailed, point-by-point response to all comments. For clarity, the reviewer’s comments are presented in italics , followed by our responses. All modifications have been incorporated into the revised manuscript, and the relevant sections have been updated accordingly. Comment 1: “In Table 1, a column should be added to indicate whether the study involves combination with other therapies, specifying the applied therapeutic types. Besides, please confirm whether the corresponding references should be provided.” Response: Thank you for this valuable suggestion. We have added an additional column titled “Combination with Other Therapies” in Table 1, specifying whether each study involved additional interventions and the type of therapy applied (e.g., thrombolysis, mechanical thrombectomy, neuroprotective agents). All references have been retained and clearly linked to the respective studies in the table. Comment 2: “The title is ‘Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach,’ whereas the detailed discussion on oxygen-delivering nanobubbles was lacking. A summary of the types of nanobubbles and the agents employed to improve oxygenation should be added in the ‘4. Discussion’ section.” Response: We appreciate your feedback. We have expanded the Discussion section by adding a new sub-section ( 4.5 Types of Nanobubbles and Oxygenation Agents ) that provides a detailed summary of the main types of oxygen-delivering nanobubbles (liposomal, perfluorocarbon-based, protein-based, and functionalized nanobubbles) and commonly used oxygenation agents such as perfluorocarbons and hemoglobin-based carriers. Comment 3: “The challenges in clinical translation and the potential strategies to overcome them should be discussed.” Response: Thank you for this important suggestion. We have included another new sub-section ( 4.6 Challenges in Clinical Translation and Potential Strategies ) in the Discussion, which outlines the major challenges—such as formulation variability, safety concerns, regulatory barriers, and targeted delivery limitations—and proposes potential strategies to address these issues, including standardization, combination therapies, real-time imaging, and cost-effective production methods. Comment 4: “Are the rationale for, and objectives of, the Systematic Review clearly stated?” Response: We appreciate this positive comment and confirm that the rationale and objectives remain clearly stated in the revised manuscript. Comment 5: “Are sufficient details of the methods and analysis provided to allow replication by others?” Response: Thank you. We have reviewed the Methods section and believe that the details provided are sufficient for replication. No changes we make for this section. Comment 6: “Is the statistical analysis and its interpretation appropriate?” Response: We appreciate the reviewer’s positive assessment regarding the appropriateness of the statistical analysis and its interpretation. No changes we make in this section. Comment 7: “Are the conclusions drawn adequately supported by the results presented in the review?” Response: We have strengthened the Discussion and Conclusion sections in the revised manuscript to ensure that the conclusions are fully supported by the findings and the additional insights provided in response to your comments. Additional: We alsonwould like to sincerely thank the reviewer for their valuable comments and constructive suggestions, which have significantly improved the quality and clarity of our manuscript. We have carefully revised the manuscript in response to each point raised. For clarity, the reviewer’s comments are presented in italics , followed by our responses. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Morris K. Reviewer Report For: Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach [version 3; peer review: 2 approved] . F1000Research 2025, 14 :406 ( https://doi.org/10.5256/f1000research.181912.r386117 ) The direct URL for this report is: https://f1000research.com/articles/14-406/v2#referee-response-386117 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 29 May 2025 Kevin Morris , Maharashtra University of Health Sciences (MUHS), Nashik, India Approved VIEWS 0 https://doi.org/10.5256/f1000research.181912.r386117 The authors have done a decent job in ... Continue reading READ ALL The authors have done a decent job in revising the manuscript and updating from the previous version. Competing Interests: No competing interests were disclosed. Reviewer Expertise: Neurology, Nanotechnology, internal medicine I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Morris K. Reviewer Report For: Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach [version 3; peer review: 2 approved] . F1000Research 2025, 14 :406 ( https://doi.org/10.5256/f1000research.181912.r386117 ) The direct URL for this report is: https://f1000research.com/articles/14-406/v2#referee-response-386117 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 07 Apr 2025 Views 0 Cite How to cite this report: Morris K. Reviewer Report For: Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach [version 3; peer review: 2 approved] . F1000Research 2025, 14 :406 ( https://doi.org/10.5256/f1000research.178993.r379768 ) The direct URL for this report is: https://f1000research.com/articles/14-406/v1#referee-response-379768 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 10 May 2025 Kevin Morris , Maharashtra University of Health Sciences (MUHS), Nashik, India Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.178993.r379768 The authors have done a decent job on a novel topic. However there are few things that need to be addressed before indexing 1. Clarify search strategy and add Boolean operators to allow for a more comprehensive search strategy ... Continue reading READ ALL The authors have done a decent job on a novel topic. However there are few things that need to be addressed before indexing 1. Clarify search strategy and add Boolean operators to allow for a more comprehensive search strategy for other researchers. 2. Add meta-analysis if possible (even limited), 3. Provide tables summarizing study characteristics and outcomes to remove any doubts about bias in study selection. 4. Correct minor language issues. 5. A STANDARD FORM is mentioned but not provided nor any link to the said form is given to check if what is being claimed is true and correct. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Partly Is the statistical analysis and its interpretation appropriate? Partly Are the conclusions drawn adequately supported by the results presented in the review? Partly If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) No Competing Interests: No competing interests were disclosed. Reviewer Expertise: Neurology, Nanotechnology, internal medicine I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Morris K. Reviewer Report For: Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach [version 3; peer review: 2 approved] . F1000Research 2025, 14 :406 ( https://doi.org/10.5256/f1000research.178993.r379768 ) The direct URL for this report is: https://f1000research.com/articles/14-406/v1#referee-response-379768 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 28 May 2025 Suryanti Suryanti , Lincoln University College, Petaling Jaya, Malaysia 28 May 2025 Author Response We sincerely thank the reviewer for their valuable comments. The following revisions have been made: The search strategy has been clarified and now includes Boolean operators for better ... Continue reading We sincerely thank the reviewer for their valuable comments. The following revisions have been made: The search strategy has been clarified and now includes Boolean operators for better reproducibility. Due to significant heterogeneity, a meta-analysis was not feasible; this has been explained in the methods. Two tables summarizing study characteristics and key outcomes have been added to increase transparency. The manuscript has been reviewed and edited for grammar and clarity. The standardized data extraction form is now included as Supplementary File 1 and referenced in the text. We believe these changes address the reviewer’s concerns and enhance the scientific value of our work. Regards, Suryanti Chan (corresponding author) We sincerely thank the reviewer for their valuable comments. The following revisions have been made: The search strategy has been clarified and now includes Boolean operators for better reproducibility. Due to significant heterogeneity, a meta-analysis was not feasible; this has been explained in the methods. Two tables summarizing study characteristics and key outcomes have been added to increase transparency. The manuscript has been reviewed and edited for grammar and clarity. The standardized data extraction form is now included as Supplementary File 1 and referenced in the text. We believe these changes address the reviewer’s concerns and enhance the scientific value of our work. Regards, Suryanti Chan (corresponding author) Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 28 May 2025 Suryanti Suryanti , Lincoln University College, Petaling Jaya, Malaysia 28 May 2025 Author Response We sincerely thank the reviewer for their valuable comments. The following revisions have been made: The search strategy has been clarified and now includes Boolean operators for better ... Continue reading We sincerely thank the reviewer for their valuable comments. The following revisions have been made: The search strategy has been clarified and now includes Boolean operators for better reproducibility. Due to significant heterogeneity, a meta-analysis was not feasible; this has been explained in the methods. Two tables summarizing study characteristics and key outcomes have been added to increase transparency. The manuscript has been reviewed and edited for grammar and clarity. The standardized data extraction form is now included as Supplementary File 1 and referenced in the text. We believe these changes address the reviewer’s concerns and enhance the scientific value of our work. Regards, Suryanti Chan (corresponding author) We sincerely thank the reviewer for their valuable comments. The following revisions have been made: The search strategy has been clarified and now includes Boolean operators for better reproducibility. Due to significant heterogeneity, a meta-analysis was not feasible; this has been explained in the methods. Two tables summarizing study characteristics and key outcomes have been added to increase transparency. The manuscript has been reviewed and edited for grammar and clarity. The standardized data extraction form is now included as Supplementary File 1 and referenced in the text. We believe these changes address the reviewer’s concerns and enhance the scientific value of our work. Regards, Suryanti Chan (corresponding author) Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 3 VERSION 3 PUBLISHED 07 Apr 2025 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 3 (revision) 19 Aug 25 read Version 2 (revision) 20 May 25 read read Version 1 07 Apr 25 read Kevin Morris , Maharashtra University of Health Sciences (MUHS), Nashik, India Fang Fang , National University of Singapore, Singapore, Singapore Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Fang F. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 02 Sep 2025 | for Version 3 Fang Fang , National University of Singapore, Singapore, Singapore 0 Views copyright © 2025 Fang F. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The authors have addressed my previous concerns appropriately and carefully. I recommend the manuscript for indexing. Competing Interests No competing interests were disclosed. Reviewer Expertise Nanomedicine, Drug Delivery, Self-Assembly, Disease Theranostics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Fang F. Peer Review Report For: Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach [version 3; peer review: 2 approved] . F1000Research 2025, 14 :406 ( https://doi.org/10.5256/f1000research.186612.r406872) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-406/v3#referee-response-406872 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Fang F. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 14 Aug 2025 | for Version 2 Fang Fang , National University of Singapore, Singapore, Singapore 0 Views copyright © 2025 Fang F. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions In this manuscript, Hamzah et al. reviewed the role of oxygen-delivering nanobubbles in stroke therapy. The review is systematic and comprehensive, and the method is rigorous and clearly described. After addressing the following minor issues, it could be considered for indexing. In Table 1, a column should be added to indicate whether the study involves combination with other therapies, specifying the applied therapeutic types. Besides, please confirm whether the corresponding references should be provided. The title is “Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach,” whereas the detailed discussion on oxygen-delivering nanobubbles was lacking. A summary of the types of nanobubbles and the agents employed to improve oxygenation should be added in the “4. Discussion” section. The challenges in clinical translation and the potential strategies to overcome them should be discussed. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? Yes Are the conclusions drawn adequately supported by the results presented in the review? Partly If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable Competing Interests No competing interests were disclosed. Reviewer Expertise Nanomedicine, Drug Delivery, Self-Assembly, Disease Theranostics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 05 Sep 2025 Suryanti Suryanti, Lincoln University College, Petaling Jaya, Malaysia We would like to sincerely thank the reviewer for their valuable comments and constructive suggestions, which have significantly improved the quality and clarity of our manuscript. We have carefully revised the manuscript in response to each point raised. Below, we provide a detailed, point-by-point response to all comments. For clarity, the reviewer’s comments are presented in italics , followed by our responses. All modifications have been incorporated into the revised manuscript, and the relevant sections have been updated accordingly. Comment 1: “In Table 1, a column should be added to indicate whether the study involves combination with other therapies, specifying the applied therapeutic types. Besides, please confirm whether the corresponding references should be provided.” Response: Thank you for this valuable suggestion. We have added an additional column titled “Combination with Other Therapies” in Table 1, specifying whether each study involved additional interventions and the type of therapy applied (e.g., thrombolysis, mechanical thrombectomy, neuroprotective agents). All references have been retained and clearly linked to the respective studies in the table. Comment 2: “The title is ‘Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach,’ whereas the detailed discussion on oxygen-delivering nanobubbles was lacking. A summary of the types of nanobubbles and the agents employed to improve oxygenation should be added in the ‘4. Discussion’ section.” Response: We appreciate your feedback. We have expanded the Discussion section by adding a new sub-section ( 4.5 Types of Nanobubbles and Oxygenation Agents ) that provides a detailed summary of the main types of oxygen-delivering nanobubbles (liposomal, perfluorocarbon-based, protein-based, and functionalized nanobubbles) and commonly used oxygenation agents such as perfluorocarbons and hemoglobin-based carriers. Comment 3: “The challenges in clinical translation and the potential strategies to overcome them should be discussed.” Response: Thank you for this important suggestion. We have included another new sub-section ( 4.6 Challenges in Clinical Translation and Potential Strategies ) in the Discussion, which outlines the major challenges—such as formulation variability, safety concerns, regulatory barriers, and targeted delivery limitations—and proposes potential strategies to address these issues, including standardization, combination therapies, real-time imaging, and cost-effective production methods. Comment 4: “Are the rationale for, and objectives of, the Systematic Review clearly stated?” Response: We appreciate this positive comment and confirm that the rationale and objectives remain clearly stated in the revised manuscript. Comment 5: “Are sufficient details of the methods and analysis provided to allow replication by others?” Response: Thank you. We have reviewed the Methods section and believe that the details provided are sufficient for replication. No changes we make for this section. Comment 6: “Is the statistical analysis and its interpretation appropriate?” Response: We appreciate the reviewer’s positive assessment regarding the appropriateness of the statistical analysis and its interpretation. No changes we make in this section. Comment 7: “Are the conclusions drawn adequately supported by the results presented in the review?” Response: We have strengthened the Discussion and Conclusion sections in the revised manuscript to ensure that the conclusions are fully supported by the findings and the additional insights provided in response to your comments. Additional: We alsonwould like to sincerely thank the reviewer for their valuable comments and constructive suggestions, which have significantly improved the quality and clarity of our manuscript. We have carefully revised the manuscript in response to each point raised. For clarity, the reviewer’s comments are presented in italics , followed by our responses. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Fang F. Peer Review Report For: Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach [version 3; peer review: 2 approved] . F1000Research 2025, 14 :406 ( https://doi.org/10.5256/f1000research.181912.r400623) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-406/v2#referee-response-400623 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Morris K. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 29 May 2025 | for Version 2 Kevin Morris , Maharashtra University of Health Sciences (MUHS), Nashik, India 0 Views copyright © 2025 Morris K. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The authors have done a decent job in revising the manuscript and updating from the previous version. Competing Interests No competing interests were disclosed. Reviewer Expertise Neurology, Nanotechnology, internal medicine I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Morris K. Peer Review Report For: Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach [version 3; peer review: 2 approved] . F1000Research 2025, 14 :406 ( https://doi.org/10.5256/f1000research.181912.r386117) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-406/v2#referee-response-386117 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Morris K. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 10 May 2025 | for Version 1 Kevin Morris , Maharashtra University of Health Sciences (MUHS), Nashik, India 0 Views copyright © 2025 Morris K. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The authors have done a decent job on a novel topic. However there are few things that need to be addressed before indexing 1. Clarify search strategy and add Boolean operators to allow for a more comprehensive search strategy for other researchers. 2. Add meta-analysis if possible (even limited), 3. Provide tables summarizing study characteristics and outcomes to remove any doubts about bias in study selection. 4. Correct minor language issues. 5. A STANDARD FORM is mentioned but not provided nor any link to the said form is given to check if what is being claimed is true and correct. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Partly Is the statistical analysis and its interpretation appropriate? Partly Are the conclusions drawn adequately supported by the results presented in the review? Partly If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) No Competing Interests No competing interests were disclosed. Reviewer Expertise Neurology, Nanotechnology, internal medicine I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 28 May 2025 Suryanti Suryanti, Lincoln University College, Petaling Jaya, Malaysia We sincerely thank the reviewer for their valuable comments. The following revisions have been made: The search strategy has been clarified and now includes Boolean operators for better reproducibility. Due to significant heterogeneity, a meta-analysis was not feasible; this has been explained in the methods. Two tables summarizing study characteristics and key outcomes have been added to increase transparency. The manuscript has been reviewed and edited for grammar and clarity. The standardized data extraction form is now included as Supplementary File 1 and referenced in the text. We believe these changes address the reviewer’s concerns and enhance the scientific value of our work. Regards, Suryanti Chan (corresponding author) View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Morris K. Peer Review Report For: Review the role of oxygen-delivering nanobubbles in stroke therapy: A novel approach [version 3; peer review: 2 approved] . F1000Research 2025, 14 :406 ( https://doi.org/10.5256/f1000research.178993.r379768) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-406/v1#referee-response-379768 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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