Chronic wounds remain a major clinical challenge due to persistent inflammation, excessive oxidative stress, and impaired tissue regeneration. Herein, we developed a multifunctional hydrogel dressing (GX/ML) by integrating a reactive oxygen species (ROS)-responsive dynamic borate ester cross-linking network with electrocatalytic MXene nanosheets and anti-inflammatory luteolin. The hydrogel enables real-time monitoring of wound inflammation through electrochemical sensing of H2O2 levels, while on-demand drug release is triggered by either high ROS or near-infrared irradiation. In vitro and in vivo results demonstrated exceptional ROS-scavenging capability, efficient antibacterial activity (>96% against S. aureus and E. coli), and promotion of macrophage polarization toward the pro-healing M2 phenotype. In a diabetic mouse wound model, the GX/ML hydrogel accelerated wound closure (98.1% healing rate by day 19), enhanced angiogenesis, collagen deposition, and re-epithelialization, and modulated immune responses via cytokine signaling pathways (e.g., NF-κB and NOD-like receptor pathways). Transcriptomic analysis confirmed regulation of genes related to immune inflammation and tissue remodeling. This work provides a synergistic strategy through a smart hydrogel platform that integrates real-time inflammatory monitoring with condition-triggered drug release, offering a feedback-responsive approach for chronic wound management.
| [1] |
V. Falanga, R. R. Isseroff, A. M. Soulika, et al., “Chronic Wounds,” Nature Reviews Disease Primers 8 (2022): 50.
|
| [2] |
F. Huang, X. Lu, Y. Yang, et al., “Microenvironment-Based Diabetic Foot Ulcer Nanomedicine,” Advanced Science 10 (2023): 2203308.
|
| [3] |
J. Zhu, F. Xia, S. Wang, Y. Guan, F. Hu, and F. Yu, “Recent Advances in Nanomaterials and Their Mechanisms for Infected Wounds Management,” Materials Today Bio 31 (2025): 101553.
|
| [4] |
X. Qi, Y. Xiang, Y. Li, et al., “An ATP-Activated Spatiotemporally Controlled Hydrogel Prodrug System for Treating Multidrug-Resistant Bacteria-Infected Pressure Ulcers,” Bioactive Materials 45 (2025): 301–321.
|
| [5] |
Q. Su, J. Wang, Y. Huangfu, et al., “An Off-the-Shelf Artificial Proregenerative Macrophage for Pressure Ulcer Treatment,” Advanced Science 12 (2025): 2415886.
|
| [6] |
O. A. Peña and P. Martin, “Cellular and Molecular Mechanisms of Skin Wound Healing,” Nature Reviews Molecular Cell Biology 25 (2024): 599–616.
|
| [7] |
S. A. Eming, P. Martin, and M. Tomic-Canic, “Wound Repair and Regeneration: Mechanisms, Signaling, and Translation,” Science Translational Medicine 6 (2014): 265sr6.
|
| [8] |
Z. Cheng, M. Kang, X. Peng, et al., “Self-Assembled Eutectogel With Cell Permeation and Multiple Anti-Inflammatory Abilities for Treating Chronic Periodontitis,” Advanced Materials 37 (2025): 2412866.
|
| [9] |
H. Sies and D. P. Jones, “Reactive Oxygen Species (ROS) as Pleiotropic Physiological Signalling Agents,” Nature Reviews Molecular Cell Biology 21 (2020): 363–383.
|
| [10] |
P. Wang, Q. Gong, J. Hu, X. Li, and X. Zhang, “Reactive Oxygen Species (ROS)-Responsive Prodrugs, Probes, and Theranostic Prodrugs: Applications in the ROS-Related Diseases,” Journal of Medicinal Chemistry 64 (2021): 298–325.
|
| [11] |
C. Xue, J. Tian, Z. Cui, et al., “Reactive Oxygen Species (ROS)-Mediated M1 Macrophage-Dependent Nanomedicine Remodels Inflammatory Microenvironment for Osteoarthritis Recession,” Bioactive Materials 33 (2024): 545–561.
|
| [12] |
A. Chen, H. Huang, S. Fang, and Q. Hang, “ROS: A “Booster” for Chronic Inflammation and Tumor Metastasis,” Biochimica et Biophysica Acta (BBA)—Reviews on Cancer 1879 (2024): 189175.
|
| [13] |
S. Lou, J. Ma, P. Fu, et al., “Lung-Penetrating Biomimetic Extracellular Vesicle Spherical Nucleic Acids for Pulmonary Fibrosis Therapy Through ROS Scavenging and Anti-Inflammatory Effects,” Aggregate 6 (2025): e70086.
|
| [14] |
Q. Zhou, Y. Zhuang, X. Deng, et al., “Hydrogel-Based ROS-Regulating Strategy: Reprogramming the Oxidative Stress Imbalance in Advanced Diabetic Wound Repair,” Advanced Materials 38 (2025): e12719.
|
| [15] |
Y. Li, Y. Yang, H. Zhang, et al., “Self-Assembled Nanocomplexes of Oligomerized Catechins and Deoxyribonuclease-I for Synergistically Enhancing Diabetic Wound Healing,” Aggregate 7 (2026): e70235.
|
| [16] |
S. Baddi, A. Y. Dang-i, F. Gao, X. Qiu, and C. Feng, “Physical Strategies to Engineer Supramolecular Composite Hydrogels for Advanced Biomedical Applications,” Progress in Materials Science 151 (2025): 101428.
|
| [17] |
X. Ning, H. Lu, H. Zeng, Z. Zhou, and P. Hu, “Multifunctional Self-Healing Hydrogels for Chronic Wound Repair: Design, Mechanisms, and Applications,” Journal of Controlled Release 388 (2025): 114282.
|
| [18] |
S. Correa, A. K. Grosskopf, H. Lopez Hernandez, et al., “Translational Applications of Hydrogels,” Chemical Reviews 121 (2021): 11385–11457.
|
| [19] |
J. Zhang, J. Zhong, B. Liang, et al., “Robust Injectable Hydrogels for Hemophilic Arthropathy via Anti-Inflammation, Iron Removal and Cartilage Protection,” Advanced Functional Materials 35 (2025): 2500271.
|
| [20] |
X. Zhu, J. Ma, D. Zhang, et al., “Mechanically Active Adhesive and NIR-II-Activated Zwitterionic Hydrogel for Infected Maxillofacial Wound Repair and Abscess Elimination,” Aggregate 7 (2026): e70309.
|
| [21] |
Y. Zhang, L. Liu, J. Xu, et al., “Cationic Composite Hydrogel With Sustained Self-Infrared Thermal Effects for Pain Relief, Anti-Inflammation, and Accelerated Repair of Tendon Injuries,” Chemical Engineering Journal 512 (2025): 162257.
|
| [22] |
H. Han, Z. Wang, T. Wu, et al., “Dual-Crosslinked Injectable Polysaccharide-Based Hydrogel With Synergistic Photothermal-Controlled Release of Black Phosphorus-Baicalein for Accelerating Wound Healing,” Carbohydrate Polymers 372 (2026): 124532.
|
| [23] |
H. Ji, Y. Wang, K. Yao, et al., “Engineering an Anaerobic Microenvironment to Empower Hydrogenase-Catalyzed Hydrogen Therapy for Diabetic Wound Healing,” Aggregate 7 (2026): e70285.
|
| [24] |
P. Dhanraj, K. Boodhoo, and M. van de Vyver, “Delayed Immune Response Upon Injury in Diabetic Wounds Impedes Healing,” Immunity, Inflammation and Disease 13 (2025): e70142.
|
| [25] |
X. Zhao, H. Xu, Y. Sun, Y. Yang, and B. Guo, “Self-Adaptive Wound Dressings for Wound Healing and Repair,” Advanced Materials 38 (2026): e15854.
|
| [26] |
R. Dong and B. Guo, “Smart Wound Dressings for Wound Healing,” Nano Today 41 (2021): 101290.
|
| [27] |
R. Batra, L. Song, and R. Ramprasad, “Emerging Materials Intelligence Ecosystems Propelled by Machine Learning,” Nature Reviews Materials 6 (2021): 655–678.
|
| [28] |
T. K. N. Duong, T. T. Truong, T. N. L. Phan, et al., “Hydrogel-Based Smart Materials for Wound Healing and Sensing,” Aggregate 6 (2025): e70047.
|
| [29] |
M. Hunt, M. Torres, E. Bachar-Wikstrom, and J. D. Wikstrom, “Cellular and Molecular Roles of Reactive Oxygen Species in Wound Healing,” Communications Biology 7 (2024): 1534.
|
| [30] |
Y. Xiong, Q.-P. Wu, H. Wang, M.-A. Shahbazi, and B.-B. Mi, “ROS-Responsive Drug Delivery Systems for Chronic Wound Healing: Advances, Challenges, and Translational Perspectives,” Military Medical Research 13 (2026): 100019.
|
| [31] |
X. Duan, X. Yang, N. Mou, et al., “Reactive Oxygen Species-Triggered Carbon Dots-Based Biomimetic Nanotheranostic Agents for Atherosclerosis Management,” Advanced Functional Materials 34 (2024): 2405629.
|
| [32] |
X. Ge, L. Su, Z. Chen, et al., “A Radio-Pharmaceutical Fluorescent Probe for Synergistic Cancer Radiotherapy and Ratiometric Imaging of Tumor Reactive Oxygen Species,” Angewandte Chemie International Edition 62 (2023): e202305744.
|
| [33] |
K. Yan, A. C. Sedgwick, Y. Zang, et al., “Sensors, Imaging Agents, and Theranostics to Help Understand and Treat Reactive Oxygen Species Related Diseases,” Small Methods 3 (2019): 1900013.
|
| [34] |
L. He, Z. Ge, R. Teng, et al., “Machine Learning-Assisted Real-Time Inflammation Monitoring and Optimal Treatment of Diabetic Wounds Based on a Ratiometric Fluorescent Sensing Peptide Hydrogel,” Nano Letters 25 (2025): 13284–13293.
|
| [35] |
Z. Yang, Y. Dai, C. Yin, et al., “Activatable Semiconducting Theranostics: Simultaneous Generation and Ratiometric Photoacoustic Imaging of Reactive Oxygen Species in Vivo,” Advanced Materials 30 (2018): 1707509.
|
| [36] |
S. Chi, Y. Li, T. Ye, et al., “Energy Reconversion of Ultrasound on a Piezoelectric Hydrogel Promotes ROS/CO Generation and Wound Self-Closure for Infected Chronic Wound Healing,” Matter 8 (2025): 101989.
|
| [37] |
J. Xia, J. Wang, F. Liu, et al., “Red/NIR-I-Fluorescence Carbon Dots Based on Rhein With Active Oxygen Scavenging and Colitis Targeting for UC Therapeutics,” Advanced Healthcare Materials 13 (2024): 2304674.
|
| [38] |
X. Li, Y. Liu, X. Qi, et al., “Sensitive Activatable Nanoprobes for Real-Time Ratiometric Magnetic Resonance Imaging of Reactive Oxygen Species and Ameliorating Inflammation in Vivo,” Advanced Materials 34 (2022): 2109004.
|
| [39] |
J. Y. Park, S. M. Park, T. S. Lee, et al., “Innovations in Nuclear Medicine Imaging for Reactive Oxygen Species: Applications and Radiopharmaceuticals,” Antioxidants 13 (2024): 1254.
|
| [40] |
S. Liu, W. Dong, H. Gao, Z. Song, and Z. Cheng, “Near-Infrared-II Fluorescent Probes for Analytical Applications: From in Vitro Detection to in Vivo Imaging Monitoring,” Accounts of Chemical Research 58 (2025): 543–554.
|
| [41] |
Y. Zhang, X. Zhang, H. Yang, et al., “Advanced Biotechnology-Assisted Precise Sonodynamic Therapy,” Chemical Society Reviews 50 (2021): 11227–11248.
|
| [42] |
C. He, P. Feng, M. Hao, et al., “Nanomaterials in Antibacterial Photodynamic Therapy and Antibacterial Sonodynamic Therapy,” Advanced Functional Materials 34 (2024): 2402588.
|
| [43] |
M. Chu, Y. Zhang, C. Ji, Y. Zhang, Q. Yuan, and J. Tan, “DNA Nanomaterial-Based Electrochemical Biosensors for Clinical Diagnosis,” ACS Nano 18 (2024): 31713–31736.
|
| [44] |
A. Bocan, R. Siavash Moakhar, C. del Real Mata, et al., “Machine-Learning-Aided Advanced Electrochemical Biosensors,” Advanced Materials 37 (2025): 2417520.
|
| [45] |
L. Huang, Y. Zhou, X. Hu, and Z. Yang, “Emerging Combination of Hydrogel and Electrochemical Biosensors,” Small 21 (2025): 2409711.
|
| [46] |
C. Ye, H. Lukas, M. Wang, Y. Lee, and W. Gao, “Nucleic Acid-Based Wearable and Implantable Electrochemical Sensors,” Chemical Society Reviews 53 (2024): 7960–7982.
|
| [47] |
H. Shafique, J. de Vries, J. Strauss, A. Khorrami Jahromi, R. Siavash Moakhar, and S. Mahshid, “Advances in the Translation of Electrochemical Hydrogel-Based Sensors,” Advanced Healthcare Materials 12 (2023): 2201501.
|
| [48] |
P. GhavamiNejad, A. GhavamiNejad, H. Zheng, K. Dhingra, M. Samarikhalaj, and M. Poudineh, “A Conductive Hydrogel Microneedle-Based Assay Integrating PEDOT:PSS and Ag-Pt Nanoparticles for Real-Time, Enzyme-Less, and Electrochemical Sensing of Glucose,” Advanced Healthcare Materials 12 (2023): 2202362.
|
| [49] |
Z. Wang, Z. Lin, X. Mei, et al., “Engineered Living Systems Based on Gelatin: Design, Manufacturing, and Applications,” Advanced Materials 37 (2025): 2416260.
|
| [50] |
H. Wei, H. Jing, C. Cheng, Y. Liu, and J. Hao, “A Biomimetic One-Stone-Two-Birds Hydrogel With Electroconductive, Photothermally Antibacterial and Bioadhesive Properties for Skin Tissue Regeneration and Mechanosensation Restoration,” Advanced Functional Materials 35 (2025): 2417280.
|
| [51] |
Y.-L. Lin, S. Zheng, C.-C. Chang, L.-R. Lee, and J.-T. Chen, “Light-Responsive MXenegel via Interfacial Host–Guest Supramolecular Bridging,” Nature Communications 15 (2024): 916.
|
| [52] |
H. Riazi, M. Anayee, K. Hantanasirisakul, et al., “Surface Modification of a MXene by an Aminosilane Coupling Agent,” Advanced Materials Interfaces 7 (2020): 1902008.
|
| [53] |
W.-J. Zhang, S. Li, Y.-Z. Yan, et al., “Dual (pH- and ROS-) Responsive Antibacterial MXene-Based Nanocarrier for Drug Delivery,” International Journal of Molecular Sciences 23 (2022): 14925.
|
| [54] |
T. Tu, S. Zhang, T. Li, et al., “Tissue-Like Conductive Ti3C2/Sodium Alginate Hybrid Hydrogel for Electrochemical Sensing,” ACS Applied Materials & Interfaces 14 (2022): 57311–57320.
|
| [55] |
Y. Li, Y. Wang, Y. Ding, et al., “A Double Network Composite Hydrogel With Self-Regulating Cu2+/Luteolin Release and Mechanical Modulation for Enhanced Wound Healing,” ACS Nano 18 (2024): 17251–17266.
|
| [56] |
F. Gendrisch, P. R. Esser, C. M. Schempp, and U. Wölfle, “Luteolin as a Modulator of Skin Aging and Inflammation,” Biofactors 47 (2021): 170–180.
|
| [57] |
W. Fu, Z. Huang, W. Li, et al., “Copper–Luteolin Nanocomplexes for Mediating Multifaceted Regulation of Oxidative Stress, Intestinal Barrier, and Gut Microbiota in Inflammatory Bowel Disease,” Bioactive Materials 46 (2025): 118–133.
|
| [58] |
Y. Chen, W. Liu, S. Wan, et al., “Superior Synergistic Osteogenesis of MXene-Based Hydrogel Through Supersensitive Drug Release at Mild Heat,” Advanced Functional Materials 34 (2024): 2309191.
|
| [59] |
Y. Li, R. Fu, Z. Duan, C. Zhu, and D. Fan, “Adaptive Hydrogels Based on Nanozyme With Dual-Enhanced Triple Enzyme-Like Activities for Wound Disinfection and Mimicking Antioxidant Defense System,” Advanced Healthcare Materials 11 (2022): 2101849.
|
| [60] |
X. Hu, C. He, P. Zeng, et al., “Sialylated Macrophage Nano-Decoys Mitigate Inflammatory-ROS Microenvironment and Reprogram Endothelial Function in Myocardial Infarction,” Advanced Functional Materials 36 (2025): e08455.
|
| [61] |
W. Huang, Q. Guo, H. Wu, Y. Zheng, T. Xiang, and S. Zhou, “Engineered Exosomes Loaded in Intrinsic Immunomodulatory Hydrogels With Promoting Angiogenesis for Programmed Therapy of Diabetic Wounds,” ACS Nano 19 (2025): 14467–14483.
|
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