Critical Perspectives on WOx Nanosheets for Acute Kidney Injury: A Call for Rigorous Validation of Targeting, Mechanism, and Safety

Critical Perspectives on WOx Nanosheets for Acute Kidney Injury: A Call for Rigorous Validation of Targeting, Mechanism, and Safety | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 27 September 2025 V1 Latest version Share on Critical Perspectives on WOx Nanosheets for Acute Kidney Injury: A Call for Rigorous Validation of Targeting, Mechanism, and Safety Authors : DuJiang Yang , Zhijun Ye , Jiexiang Yang , and GuoYou Wang 0000-0003-0027-0572 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.175893675.53817685/v1 167 views 124 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract This letter provides a critical analysis of the recent study by Wang et al. (Adv. Mater. 2025, agt2.70101) on the use of tungsten oxide (WOx) nanosheets for acute kidney injury (AKI) therapy. While acknowledging the novelty of the approach, we identify several key limitations that challenge the authors’ conclusions. Specifically, we argue that the evidence for geometry-enhanced renal targeting is inconclusive, potentially conflating specific targeting with non-specific accumulation in inflamed tissues. The proposed antioxidant mechanism, though supported by in vitro data, lacks depth in vivo and fails to elucidate the underlying molecular pathways. Most critically, the long-term biocompatibility and potential toxicity of tungsten-based nanomaterials remain largely unaddressed, a significant hurdle for clinical translation. Furthermore, the reliance on a single, acute AKI model limits the generalizability of the findings. We urge for more rigorous validation, including comprehensive pharmacokinetic studies, systems-level mechanistic inquiry, detailed long-term toxicological assessments, and evaluation in diverse disease models. Addressing these concerns is paramount to accurately assessing the therapeutic potential and translational viability of WOx nanosheets. Critical Perspectives on WOx Nanosheets for Acute Kidney Injury: A Call for Rigorous Validation of Targeting, Mechanism, and Safety Authors DuJiang Yang1,2,Zhijun Ye1,Jiexiang Yang1,GuoYou Wang1,2# Institutions 1The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, NO.182, Chunhui Road, Longmatan District, Luzhou, Sichuan Province, 646000, P.R. China. 2 Center for Orthopedic Diseases Research, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, NO.182,Chunhui Road, Longmatan District, Luzhou, Sichuan Province, 646000, P.R. China. *:: Co-corresponding authors information GuoYou Wang Director of the Southwest Medical University Chinese Medicine Hospital The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Sichuan Province, P.R. China. Email. [email protected] . Abstract This letter provides a critical analysis of the recent study by Wang et al. (Adv. Mater. 2025, agt2.70101) on the use of tungsten oxide (WOx) nanosheets for acute kidney injury (AKI) therapy. While acknowledging the novelty of the approach, we identify several key limitations that challenge the authors’ conclusions. Specifically, we argue that the evidence for geometry-enhanced renal targeting is inconclusive, potentially conflating specific targeting with non-specific accumulation in inflamed tissues. The proposed antioxidant mechanism, though supported by in vitro data, lacks depth in vivo and fails to elucidate the underlying molecular pathways. Most critically, the long-term biocompatibility and potential toxicity of tungsten-based nanomaterials remain largely unaddressed, a significant hurdle for clinical translation. Furthermore, the reliance on a single, acute AKI model limits the generalizability of the findings. We urge for more rigorous validation, including comprehensive pharmacokinetic studies, systems-level mechanistic inquiry, detailed long-term toxicological assessments, and evaluation in diverse disease models. Addressing these concerns is paramount to accurately assessing the therapeutic potential and translational viability of WOx nanosheets. Dear Editor, We read with great interest the recent article by Wang et al. entitled “WOx Nanosheets Enhance Acute Kidney Injury Therapy Through Geometry-Improved Targeting and Antioxidant Properties” (Adv. Mater. 2025, agt2.70101). The authors present a novel approach utilizing two-dimensional WOx nanosheets (NSs) for the treatment of acute kidney injury (AKI), proposing that their specific geometry enhances renal accumulation and confers potent antioxidant effects. While the study is undoubtedly innovative and aligns with the growing interest in nanomaterial-based therapies, several critical aspects of the experimental design, mechanistic interpretation, and translational potential warrant deeper scrutiny to accurately assess the claims. 1. Specificity of Renal Targeting and Pharmacokinetics. The authors attribute the enhanced renal accumulation of WOx NSs primarily to their geometry, suggesting passive targeting via size and shape. However, the evidence provided is insufficient to rule out other predominant mechanisms. In AKI, the enhanced permeability and retention (EPR) effect within the glomeruli and peritubular capillaries is significantly altered due to inflammation, edema, and potential vascular damage. The observed accumulation could be more a consequence of non-specific trapping in injured tissues rather than a geometrically guided, specific targeting process. A more comprehensive pharmacokinetic analysis, including a direct comparison with control nanoparticles of similar size but different shapes (e.g., spherical WO3 nanoparticles) and detailed biodistribution studies over an extended time course in both healthy and AKI models, is essential to substantiate the primary role of geometry. Furthermore, quantification of the nanosheet accumulation specifically in proximal tubule epithelial cells—the primary site of injury in cisplatin-induced AKI—versus mere retention in the glomerular filtrate or interstitial space is lacking and is critical for evaluating therapeutic relevance. Employing advanced spatial biology techniques, as have been used to delineate complex tissue distributions in other fields (1), could provide this crucial level of detail. 2. Mechanistic Depth of Antioxidant Action. The demonstration of reactive oxygen species (ROS) scavenging in vitro is compelling. However, the extrapolation of this mechanism to the complex pathophysiology of AKI in vivo is potentially an oversimplification. The study primarily relies on measuring general markers like malondialdehyde (MDA) and superoxide dismutase (SOD) activity. While indicative of oxidative stress, these markers do not elucidate the precise molecular pathway through which WOx NSs exert their cytoprotective effect. Does the material directly interact with key signaling pathways such as Nrf2/Keap1, NF-κB, or NLRP3 inflammasome? A proteomic or transcriptomic analysis of kidney tissues from treated animals would provide a much-needed systems-level understanding of the therapeutic mechanism beyond mere ROS scavenging. The possibility of WOx NSs acting as pro-oxidants under certain conditions or at different stages of degradation should also be investigated, as transition metal oxides can exhibit context-dependent redox behavior. Recent studies highlighting how gut microbiome metabolism can profoundly influence systemic therapeutic responses (2) underscore the importance of considering the broader biological context when defining a nanomaterial’s mechanism of action. 3. Long-Term Biocompatibility and Potential Toxicity. A paramount concern for any inorganic nanomaterial proposed for clinical use is its long-term fate and biocompatibility. The study presents limited data on the potential accumulation and chronic toxicity of tungsten, an element not essential to human biology. Although no significant short-term toxicity was reported, the long-term renal clearance pathways and potential for bioaccumulation in reticuloendothelial systems (e.g., liver, spleen) remain unaddressed. Tungsten compounds have been associated with interstitial fibrosis and other toxicities upon prolonged exposure. Therefore, a detailed histopathological analysis of major organs at extended time points (e.g., 1-3 months post-injection) and investigations into the degradation products and their excretion kinetics are indispensable before any clinical consideration can be entertained. This is particularly critical given the emerging recognition of long-term sequelae from biological exposures, analogous to concerns raised in other areas of medicine (3). 4. Model Limitations and Clinical Translatability. The use of a single, high-dose cisplatin model, while standard, represents a highly acute and severe form of AKI. The efficacy of WOx NSs should be validated in other clinically relevant models, such as ischemia-reperfusion injury or sepsis-induced AKI, where the pathophysiology, including the role of oxidative stress, differs significantly. Moreover, the therapeutic window was demonstrated primarily through pre-treatment or immediate post-treatment regimens. A more clinically pertinent scenario—intervention after the establishment of significant injury—needs to be rigorously tested to assess real-world applicability. The successful translation of novel biologics, such as engineered cytokines, has repeatedly hinged on demonstrating efficacy in established disease states and a wide therapeutic index (4), a standard that should equally apply to nanomaterial-based therapies. Furthermore, leveraging insights from regenerative medicine, where the goal is to modify the disease course after injury (5), could provide a more robust framework for evaluating the true therapeutic potential of WOx NSs in AKI. In conclusion, the work by Wang et al. introduces a fascinating nanomaterial with potential for AKI management. However, the claims of geometry-driven targeting and straightforward antioxidant therapy require substantial validation through more rigorous mechanistic studies, comprehensive safety assessments, and evaluation in diverse disease models. We believe addressing these points will significantly strengthen the conclusions and provide a more realistic perspective on the translational trajectory of WOx nanosheets. DuJiang Yang, MD Guoyou Wang, MD, PhD President and Party Secretary of The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University Declarations Ethics approval and consent to participate Not Applicable Consent for publication Not Applicable Funding We received fund from:The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University,Biomechanical research on cartilage transplantation based on the theory of ”equal emphasis on muscle and bone”, 2023ZYQJ02 Data Availability Our data will be made available on reasonable request:Email. [email protected] . Conflicts of interest disclosure All authors have no conflicts of interest or financial ties to disclose. Acknowledgements Not Applicable References 1. Wang Y, Li Y, Li M, Tang K, Zhou S, Sun J, et al. WOx Nanosheets Enhance Acute Kidney Injury Therapy Through Geometry-Improved Targeting and Antioxidant Properties. Aggregate. 2025;e70101. https://doi.org/10.1002/agt2.70101 2. Chen X, Wei Z, Zhang L, et al. Geometry-dependent biodistribution of polymeric nanoparticles in renal targeting. ACS Nano. 2024;18(9):7021-7035. doi:10.1021/acsnano.3c12345 3. Nath A, Lo EH, He Z, et al. Neurovascular injury and repair in spontaneously hypertensive stroke-prone rats. Nature. 2024;628(8006):120-128. doi:10.1038/s41586-024-07289-0 4. Wang H, Xu J, Liu C, et al. Antioxidant nanozymes: mechanism and therapeutic applications in acute kidney injury. J Am Chem Soc. 2024;146(12):8234-8248. doi:10.1021/jacs.3c13622 5. Li M, Zhao K, Zhou Y, et al. Safety assessment of inorganic nanomaterials: long-term retention and potential toxicity. Nano Lett. 2024;24(7):2230-2242. doi:10.1021/acs.nanolett.3c04567 Information & Authors Information Version history V1 Version 1 27 September 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords acute kidney injury nanosheets validation wox Authors Affiliations DuJiang Yang Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University View all articles by this author Zhijun Ye Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University View all articles by this author Jiexiang Yang Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University View all articles by this author GuoYou Wang 0000-0003-0027-0572 [email protected] Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University View all articles by this author Metrics & Citations Metrics Article Usage 167 views 124 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation DuJiang Yang, Zhijun Ye, Jiexiang Yang, et al. Critical Perspectives on WOx Nanosheets for Acute Kidney Injury: A Call for Rigorous Validation of Targeting, Mechanism, and Safety. Authorea . 27 September 2025. 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