Targeting oxidative damage in diabetic foot ulcers: integrative strategies involving antioxidant drugs and nanotechnologies

Abstract

Foot ulcerations in patients with diabetes are common and severe, typically caused by infection and chronic inflammation. Poor blood circulation and neuropathy impair the body’s ability to heal wounds effectively, creating a conducive environment for ulcers. Excessive reactive oxygen species contribute to ulcer development by damaging cellular structures and hindering wound healing. The administration of antioxidants can protect cells from oxidative damage and promote wound recovery. Antioxidants such as epidermal growth factors, flavonoid hesperidin, alpha-lipoic acid, and N-acetylcysteine effectively reduce oxidative stress. Encapsulating various drugs into nanoparticles and targeting carriers such as hydrogels, metal–organic frameworks, and nanohydrogels can improve their therapeutic effects. Nanotechnologies have been shown to boost tissue regeneration by modifying biomaterial properties, modulating signal release, and targeting key factors. Here, we describe the occurrence and development of diabetic foot ulcers (DFUs), emphasizing the role of oxidative damage in these processes. This review summarizes the strategy for targeting oxidative damage in DFUs using nanotechnology-loaded antioxidant drugs. This review advocates for the use of personalized biomaterials in treating DFUs and provides a theoretical basis for their potential clinical and translational applications.

Keywords

Diabetes / Oxidative stress / Antioxidant treatment / Diabetic foot ulcers / Wound healing / Inflammation

References

[1] Kasowanjete P, Abrahamse H, Houreld NN. Photobiomodulation at 660 nm stimulates in vitro diabetic wound healing via the Ras/MAPK pathway. Cells 2023; 12: 18. https://doi.org/10.3390/cells12071080.

[2] Boulton AJ, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J. The global burden of diabetic foot disease. Lancet (London, England) 2005; 366: 1719-24. https://doi.org/10.1016/S0140-6736(05)67698-2.

[3] Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the global burden of disease study 2021. Lancet (London, England) 2023; 402: 203-34. https://doi.org/10.1016/S0140-6736(23)01301-6.

[4] National expert consensus on the diagnosis and surgical treatment of diabetic foot ulcers complicated with lower extremity vasculopathy (2024 version). Zhonghua shao shang yu chuang mian xiu fu za zhi 2024; 40: 206-20. https://doi.org/10.3760/cma.j.cn501225-20231122-00202.

[5] Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the international diabetes federation diabetes atlas, 9th edition. Diabetes Res Clin Pract 2019; 157: 10.

[6] Guo L, Xiao D, Xing H, Yang G, Yang X. Engineered exosomes as a prospective therapy for diabetic foot ulcers. Burns & Trauma 2024; 12: tkae023. https://doi.org/10.1093/burnst/tkae023.

[7] Roglic G. WHO global report on diabetes: a summary. International Journal of Noncommunicable Diseases 2016; 1: 3-8. https://doi.org/10.4103/2468-8827.184853.

[8] Huang F, Lu X, Yang Y, Yang Y, Li Y, Kuai L, et al. Microenvironment-based diabetic foot ulcer nanomedicine. Adv Sci (Weinh) 2023; 10: e2203308. https://doi.org/10.1002/advs.202203308.

[9] Wang Y, Zhang Y, Yang YP, Jin MY, Huang S, Zhuang ZM, et al. Versatile dopamine-functionalized hyaluronic acid-recombinant human collagen hydrogel promoting diabetic wound healing via inflammation control and vascularization tissue regeneration. Bioact Mater 2024; 35: 330-45. https://doi.org/10.1016/j.bioactmat.2024.02.010.

[10] Senneville É, Albalawi Z, van Asten SA, Abbas ZG, Allison G, Aragón-Sánchez J, et al. IWGDF/IDSA guidelines on the diagnosis and treatment of diabetes-related foot infections (IWGDF/IDSA 2023). Clin Infect Dis 2023; 79: 286. https://doi.org/10.1093/cid/ciad527.

[11] Liu EH, Hu XJ, Zhang WK, Xiao W, Shen YT, Luo Y, et al. Efficacy and safety of ultrasound-assisted wound debridement in the treatment of diabetic foot ulcers: a systematic review and meta-analysis of 11 randomized controlled trials. Front Endocrinol 2024; 15: 9.

[12] Ren YP, Zhou XL, Gao XJ, Si JJ, Ren WH, Li CX, et al. Ultra-high antioxidant, anti-apoptosis and pro-angiogenesis effect of Mo2C nanosheets for treatment of diabetic wounds. Nano Today 2024; 55: 102202. https://doi.org/10.1016/j.nantod.2024.102202.

[13] Falanga V, Isseroff RR, Soulika AM, Romanelli M, Margolis D, Kapp S, et al. Chronic wounds. Nat Rev Dis Primers 2022; 8: 50. https://doi.org/10.1038/s41572-022-00377-3.

[14] Zhang Y, Lazzarini PA, McPhail SM, van Netten JJ, Armstrong DG, Pacella RE. Global disability burdens of diabetes-related lower-extremity complications in 1990 and 2016. Diabetes Care 2020; 43: 964-74. https://doi.org/10.2337/dc19-1614.

[15] Zhao Y, Zhao Y, Xu B, Liu H, Chang Q. Microenvironmental dynamics of diabetic wounds and insights for hydrogel-based therapeutics. J Tissue Eng 2024; 15: 20417314241253290. https://doi.org/10.1177/20417314241253290.

[16] Petersen BJ, Linde-Zwirble WT, Tan TW, Rothenberg GM, Salgado SJ, Bloom JD, et al. Higher rates of all-cause mortality and resource utilization during episodes-of-care for diabetic foot ulceration. Diabetes Res Clin Pract 2022; 184: 109182. https://doi.org/10.1016/j.diabres.2021.109182.

[17] Ndosi M, Wright-Hughes A, Brown S, Backhouse M, Lipsky BA, Bhogal M, et al. Prognosis of the infected diabetic foot ulcer: a 12-month prospective observational study. Diabet Med 2018; 35: 78-88. https://doi.org/10.1111/dme.13537.

[18] Isaac AL, Swartz TD, Miller ML, Short DJ, Wilson EA, Chaffo JL, et al. Lower resource utilization for patients with healed diabetic foot ulcers during participation in a prevention program with foot temperature monitoring. BMJ Open Diabetes Res Care 2020; 8: 8. https://doi.org/10.1136/bmjdrc-2020-001440.

[19] Bhargava P, Schnellmann RG. Mitochondrial energetics in the kidney. Nat Rev Nephrol 2017; 13: 629-46. https://doi.org/10.1038/nrneph.2017.107.

[20] Qi X, Cai E, Xiang Y, Zhang C, Ge X, Wang J, et al. An immunomodulatory hydrogel by hyperthermia-assisted self-cascade glucose depletion and ROS scavenging for diabetic foot ulcer wound therapeutics. Adv Mater 2023; 35: e2306632.

[21] Lomelí Martínez SM, Cortés Trujillo I, Martínez Nieto M, Mercado González AE. Periodontal disease: a silent factor in the development and progression of diabetic retinopathy. World J Diabetes 2024; 15: 1672-6. https://doi.org/10.4239/wjd.v15.i8.1672.

[22] Khorsandi K, Hosseinzadeh R, Esfahani H, Zandsalimi K, Shahidi FK, Abrahamse H. Accelerating skin regeneration and wound healing by controlled ROS from photodynamic treatment. Inflamm Regen 2022; 42: 40.

[23] Wei T, Pan T, Peng X, Zhang M, Guo R, Guo Y, et al. Janus liposozyme for the modulation of redox and immune homeostasis in infected diabetic wounds. Nat Nanotechnol 2024; 19: 1178-89. https://doi.org/10.1038/s41565-024-01660-y.

[24] Mendez D, Soñanez-Organis JG, Vazquez-Anaya G, Nakano D, Nishiyama A, Ortiz R. Exogenous thyroxine increases cardiac Nrf2 and the potential to upregulate Nrf2-mediated antioxidant defense mechanisms in insulin resistant OLETF rats. Physiology 2023; 38: 2. https://doi.org/10.1152/physiol.2023.38.S1.5732025.

[25] Senneville É, Albalawi Z, van Asten SA, Abbas ZG, Allison G, Aragón-Sánchez J, et al. IWGDF/IDSA guidelines on the diagnosis and treatment of diabetes-related foot infections (IWGDF/IDSA 2023). Diabetes Metab Res Rev 2024; 40: e3687. https://doi.org/10.1002/dmrr.3687.

[26] Armstrong DG, Swerdlow MA, Armstrong AA, Conte MS, Padula WV, Bus SA. Five year mortality and direct costs of care for people with diabetic foot complications are comparable to cancer. J Foot Ankle Res 2020; 13: 16. https://doi.org/10.1186/s13047-020-00383-2.

[27] Yadav JP, Singh AK, Grishina M, Pathak P, Verma A, Kumar V, et al. Insights into the mechanisms of diabetic wounds: pathophysiology, molecular targets, and treatment strategies through conventional and alternative therapies. Inflammopharmacology 2024; 32: 149-228. https://doi.org/10.1007/s10787-023-01407-6.

[28] Jomova K, Alomar SY, Alwasel SH, Nepovimova E, Kuca K, Valko M. Several lines of antioxidant defense against oxidative stress: antioxidant enzymes, nanomaterials with multiple enzyme-mimicking activities, and low-molecular-weight antioxidants. Arch Toxicol 2024; 98: 1323-67. https://doi.org/10.1007/s00204-024-03696-4.

[29] Wang G, Wang Y, Yang Q, Xu C, Zheng Y, Wang L, et al. Metformin prevents methylglyoxal-induced apoptosis by suppressing oxidative stress in vitro and in vivo. Cell Death Dis 2022; 13: 29. https://doi.org/10.1038/s41419-021-04478-x.

[30] Zhang PJ, Li T, Wu XY, Nice EC, Huang CH, Zhang YY. Oxidative stress and diabetes: antioxidative strategies. Front Med 2020; 14: 583-600. https://doi.org/10.1007/s11684-019-0729-1.

[31] Mohammadzadeh V, Barani M, Amiri MS, Taghavizadeh Yazdi ME, Hassanisaadi M, Rahdar A, et al. Applications of plant-based nanoparticles in nanomedicine: a review. Sustain Chem Pharm 2022; 25: 100606. https://doi.org/10.1016/j.scp.2022.100606.

[32] Gallagher KA, Mills JL, Armstrong DG, Conte MS, Kirsner RS, Minc SD, et al. Current status and principles for the treatment and prevention of diabetic foot ulcers in the cardiovascular patient population: a scientific statement from the American Heart Association. Circulation 2024; 149: e232-53. https://doi.org/10.1161/CIR.0000000000001192.

[33] AbdulRaheem Y. Unveiling the significance and challenges of integrating prevention levels in healthcare practice. J Prim Care Community Health 2023; 14: 21501319231186500. https://doi.org/10.1177/21501319231186500.

[34] McDermott K, Fang M, Boulton AJM, Selvin E, Hicks CW. Etiology, epidemiology, and disparities in the burden of diabetic foot ulcers. Diabetes Care 2023; 46: 209-21. https://doi.org/10.2337/dci22-0043.

[35] Yan L, Wang J, Cai X, Liou YC, Shen HM, Hao J, et al. Macrophage plasticity: signaling pathways, tissue repair, and regeneration. MedComm 2024; 5: e658. https://doi.org/10.1002/mco2.658.

[36] Tesfaye S, Didangelos T. Diabetic neuropathy. In: Veves A, John M. Giurini, Schermerhorn ML (ed.), The Diabetic Foot: Medical and Surgical Management. Cham: Springer, 2024. 27-46.

[37] Grannes H, Ueland T, Simeone P, Liani R, Guagnano MT, Aukrust P, et al. Liraglutide and not lifestyle intervention reduces soluble CD163 after comparable weight loss in obese participants with prediabetes or type 2 diabetes mellitus. Cardiovasc Diabetol 2024; 23: 146. https://doi.org/10.1186/s12933-024-02237-8.

[38] Burgess JL, Wyant WA, Abdo Abujamra B, Kirsner RS, Jozic I. Diabetic wound-healing science. Medicina 2021; 57: 1072. https://doi.org/10.3390/medicina57101072.

[39] de Almeida LGN, Thode H, Eslambolchi Y, Chopra S, Young D, Gill S, et al. Matrix metalloproteinases: from molecular mechanisms to physiology, pathophysiology, and pharmacology. Pharmacol Rev 2022; 74: 712-68. https://doi.org/10.1124/pharmrev.121.000349.

[40] White MJ, Briquez PS, White DA, Hubbell JA. VEGF-A, PDGF-BB and HB-EGF engineered for promiscuous super affinity to the extracellular matrix improve wound healing in a model of type 1 diabetes. NPJ Regen Med 2021; 6: 76. https://doi.org/10.1038/s41536-021-00189-1.

[41] Armstrong DG, Tan TW, Boulton AJM, Bus SA. Diabetic foot ulcers: a review. JAMA 2023; 330: 62-75. https://doi.org/10.1001/jama.2023.10578.

[42] Chen N, Deng J, Zhang Z, Feng X, Wang H, Chen J, et al. Oxidative stress-triggered pyroptosis mediates Candida albicans susceptibility in diabetic foot. Microb Pathog 2022; 172: 105765. https://doi.org/10.1016/j.micpath.2022.105765.

[43] Bessman AN, Sapico FL. Infections in the diabetic patient: the role of immune dysfunction and pathogen virulence factors. J Diabetes Complicat 1992; 6: 258-62. https://doi.org/10.1016/1056-8727(92)90062-P.

[44] Jeffcoate W, Boyko EJ, Game F, Cowled P, Senneville E, Fitridge R. Causes, prevention, and management of diabetes-related foot ulcers. Lancet Diabetes Endocrinol 2024; 12: 472-82. https://doi.org/10.1016/S2213-8587(24)00110-4.

[45] Alavi A, Sibbald RG, Mayer D, Goodman L, Botros M, Armstrong DG, et al. Diabetic foot ulcers: part I. Pathophysiology and prevention. J Am Acad Dermatol 2014; 70: 1.e1-18. quiz 19-20.

[46] Zhang G, Samarawickrama PN, Gui L, Ma Y, Cao M, Zhu H, et al. Revolutionizing diabetic foot ulcer care: the senotherapeutic approach. Aging Dis 2024; 16: 946-70. https://doi.org/10.14336/AD.2024.0065.

[47] An Y, Xu BT, Wan SR, Ma XM, Long Y, Xu Y, et al. The role of oxidative stress in diabetes mellitus-induced vascular endothelial dysfunction. Cardiovasc Diabetol 2023; 22: 237. https://doi.org/10.1186/s12933-023-01965-7.

[48] Dong Y, Wang Z. ROS-scavenging materials for skin wound healing: advancements and applications. Front Bioeng Biotechnol 2023; 11: 1304835. https://doi.org/10.3389/fbioe.2023.1304835.

[49] Ji S, Liu X, Huang J, Bao J, Chen Z, Han C, et al. Consensus on the application of negative pressure wound therapy of diabetic foot wounds. Burns Trauma 2021; 9: tkab018. https://doi.org/10.1093/burnst/tkab018.

[50] Patrianef D, Jimmy Candra P, Dedy P, Aria K. Relationship between leukocyte, ESR, and CRP infection markers with changes in wound Wagner 2 and 3 diabetic foot ulcers. Journal of Indonesian Society for Vascular and Endovascular Surgery 2020; 1: 26-29.

[51] Hicks CW, Canner JK, Sherman RL, Black JH 3rd, Lum YW, Abularrage CJ. Evaluation of revascularization benefit quartiles using the wound, ischemia, and foot infection classification system for diabetic patients with chronic limb-threatening ischemia. J Vasc Surg 2021; 74: 1232-39.e3. https://doi.org/10.1016/j.jvs.2021.03.017.

[52] Miller TA, Campbell JH, Bloom N, Wurdeman SR. Racial disparities in health care with timing to amputation following diabetic foot ulcer. Diabetes Care 2022; 45: 2336-41. https://doi.org/10.2337/dc21-2693.

[53] Zhao Z, Ji L, Zheng L, Yang L, Yuan H, Chen L, et al. Effectiveness of clinical alternatives to nerve conduction studies for screening for diabetic distal symmetrical polyneuropathy: a multicenter study. Diabetes Res Clin Pract 2016; 115: 150-6. https://doi.org/10.1016/j.diabres.2016.01.002.

[54] Yang K, Wang Y, Li YW, Chen YG, Xing N, Lin HB, et al. Progress in the treatment of diabetic peripheral neuropathy. Biomedicine Pharmacother 2022; 148: 112717. https://doi.org/10.1016/j.biopha.2022.112717.

[55] Selvarajah D, Kar D, Khunti K, Davies MJ, Scott AR, Walker J, et al. Diabetic peripheral neuropathy: advances in diagnosis and strategies for screening and early intervention. Lancet Diabetes Endocrinol 2019; 7: 938-48. https://doi.org/10.1016/S2213-8587(19)30081-6.

[56] Deng L, Du C, Song P, Chen T, Rui S, Armstrong DG, et al. The role of oxidative stress and antioxidants in diabetic wound healing. Oxidative Med Cell Longev 2021; 2021: 8852759. https://doi.org/10.1155/2021/8852759.

[57] Iqbal MJ, Kabeer A, Abbas Z, Siddiqui HA, Calina D, Sharifi-Rad J, et al. Interplay of oxidative stress, cellular communication and signaling pathways in cancer. Cell Commun Signal 2024; 22: 7. https://doi.org/10.1186/s12964-023-01398-5.

[58] Duan Y, Ren W, Xu L, Ye W, Jan YK, Pu F. The effects of different accumulated pressure-time integral stimuli on plantar blood flow in people with diabetes mellitus. BMC Musculoskelet Disord 2021; 22: 554. https://doi.org/10.1186/s12891-021-04437-9.

[59] Kim JH, Ruegger PR, Lebig EG, VanSchalkwyk S, Jeske DR, Hsiao A, et al. High levels of oxidative stress create a microenvironment that significantly decreases the diversity of the microbiota in diabetic chronic wounds and promotes biofilm formation. Front Cell Infect Microbiol 2020; 10: 259. https://doi.org/10.3389/fcimb.2020.00259.

[60] Selvarajah D, Sloan G, Teh K, Wilkinson ID, Heiberg-Gibbons F, Awadh M, et al. Structural brain alterations in key somatosensory and nociceptive regions in diabetic peripheral neuropathy. Diabetes Care 2023; 46: 777-85. https://doi.org/10.2337/dc22-1123.

[61] Fan J, Pan Q, Gao Q, Li W, Xiao F, Guo L. TSH combined with TSHR aggravates diabetic peripheral neuropathy by promoting oxidative stress and apoptosis in Schwann cells. Oxidative Med Cell Longev 2021; 2021: 2482453. https://doi.org/10.1155/2021/2482453.

[62] Hill-Briggs F, Adler NE, Berkowitz SA, Chin MH, Gary-Webb TL, Navas-Acien A, et al. Social determinants of health and diabetes: a scientific review. Diabetes Care 2020; 44: 258-79. https://doi.org/10.2337/dci20-0053.

[63] Kernan WN, Forman R, Inzucchi SE. Caring for patients with diabetes in stroke neurology. Stroke 2023; 54: 894-904. https://doi.org/10.1161/STROKEAHA.122.038163.

[64] Wang J, Chen P, Han G, Zhou Y, Xiang X, Bian M, et al. Rab32 facilitates Schwann cell pyroptosis in rats following peripheral nerve injury by elevating ROS levels. J Transl Med 2024; 22: 194. https://doi.org/10.1186/s12967-024-04999-x.

[65] Galiero R, Caturano A, Vetrano E, Beccia D, Brin C, Alfano M, et al. Peripheral neuropathy in diabetes mellitus: pathogenetic mechanisms and diagnostic options. Int J Mol Sci 2023; 24: 3554. https://doi.org/10.3390/ijms24043554.

[66] Zhuang Y, Hong Z, Wu L, Zou C, Zheng Y, Chen L, et al. Influence of age on static postural control in adults with type 2 diabetes mellitus: a cross-sectional study. Front Endocrinol (Lausanne) 2023; 14: 1242700. https://doi.org/10.3389/fendo.2023.1242700.

[67] Sloan G, Selvarajah D, Tesfaye S. Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy. Nat Rev Endocrinol 2021; 17: 400-20. https://doi.org/10.1038/s41574-021-00496-z.

[68] Vági OE, Svébis MM, Domján BA, Körei AE, Tesfaye S, Horváth VJ, et al. The association between distal symmetric polyneuropathy in diabetes with all-cause mortality-a meta-analysis. Front Endocrinol (Lausanne) 2023; 14: 1079009. https://doi.org/10.3389/fendo.2023.1079009.

[69] Jeyam A, McGurnaghan SJ, Blackbourn LAK, McKnight JM, Green F, Collier A, et al. Diabetic neuropathy is a substantial burden in people with type 1 diabetes and is strongly associated with socioeconomic disadvantage: a population-representative study from Scotland. Diabetes Care 2020; 43: 734-42. https://doi.org/10.2337/dc19-1582.

[70] Zhang J, Zhang Z, Zhang K, Ge X, Sun R, Zhai X. Early detection of type 2 diabetes risk: limitations of current diagnostic criteria. Front Endocrinol (Lausanne) 2023; 14: 1260623. https://doi.org/10.3389/fendo.2023.1260623.

[71] Hagedorn JM, Engle AM, George TK, Karri J, Abdullah N, Ovrom E, et al. An overview of painful diabetic peripheral neuropathy: diagnosis and treatment advancements. Diabetes Res Clin Pract 2022; 188: 109928. https://doi.org/10.1016/j.diabres.2022.109928.

[72] Boulton AJM, Armstrong DG, Löndahl M, Frykberg RG, Game FL, Edmonds ME, et al. in: New Evidence-Based Therapies for Complex Diabetic Foot Wounds, American Diabetes Association © 2022 by American Diabetes Association. All rights reserved. None of the contents may be reproduced without the written permission of the American Diabetes Association., Arlington (VA), 2022.

[73] Lee CG, Ciarleglio A, Edelstein SL, Crandall JP, Dabelea D, Goldberg RB, et al. Prevalence of distal symmetrical polyneuropathy by diabetes prevention program treatment group, diabetes status, duration of diabetes, and cumulative glycemic exposure. Diabetes Care 2024; 47: 810-7. https://doi.org/10.2337/dc23-2009.

[74] Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester diabetic neuropathy study. Neurology 1993; 43: 817-24. https://doi.org/10.1212/WNL.43.4.817.

[75] Jensen TS, Finnerup NB. Distal symmetric polyneuropathy in diabetes: a progressive disorder? Brain 2021; 144: 2912-4. https://doi.org/10.1093/brain/awab355.

[76] Jeon SM, Pradeep A, Chang D, McDonough L, Chen Y, Latremoliere A, et al. Skin reinnervation by collateral sprouting following spared nerve injury in mice. J Neurosci 2024; 44: e1494232024. https://doi.org/10.1523/JNEUROSCI.1494-23.2024.

[77] Mondragon N, Zito PM. Pressure Injury. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Disclosure: Patrick Zito declares no relevant financial relationships with ineligible companies.

[78] Sharma S, Rayman G. Frontiers in diagnostic and therapeutic approaches in diabetic sensorimotor neuropathy (DSPN). Front Endocrinol (Lausanne) 2023; 14: 1165505. https://doi.org/10.3389/fendo.2023.1165505.

[79] Driver VR, Fabbi M, Lavery LA, Gibbons G. The costs of diabetic foot: the economic case for the limb salvage team. J Vasc Surg 2010; 52: 17s-22. https://doi.org/10.1016/j.jvs.2010.06.003.

[80] Bell DSH.Detecting and treating the protean manifestations of diabetic autonomic neuropathy. Diabetes Obes Metab 2023; 25: 1162-73. https://doi.org/10.1111/dom.15004.

[81] Mills SA, Jobling AI, Dixon MA, Bui BV, Vessey KA, Phipps JA, et al. Fractalkine-induced microglial vasoregulation occurs within the retina and is altered early in diabetic retinopathy. Proc Natl Acad Sci USA 2021; 118:e2112561118. https://doi.org/10.1073/pnas.2112561118.

[82] Cernea S, Raz I. Management of diabetic neuropathy. Metab Clin Exp 2021; 123: 154867. https://doi.org/10.1016/j.metabol.2021.154867.

[83] Commoner B, Townsend J, Pake GE. Free radicals in biological materials. Nature 1954; 174: 689-91. https://doi.org/10.1038/174689a0.

[84] Mariadoss AVA, Sivakumar AS, Lee C-H, Kim SJ. Diabetes mellitus and diabetic foot ulcer: Etiology, biochemical and molecular based treatment strategies via gene and nanotherapy. Biomed Pharmacother 2022; 151: 113134. https://doi.org/10.1016/j.biopha.2022.113134.

[85] Chowdhury M, Nevitt S, Eleftheriadou A, Kanagala P, Esa H, Cuthbertson DJ, et al. Cardiac autonomic neuropathy and risk of cardiovascular disease and mortality in type 1 and type 2 diabetes: a meta-analysis. BMJ Open Diabetes Res Care 2021; 9: 9. https://doi.org/10.1136/bmjdrc-2021-002480.

[86] Masi S, Rizzoni D, Taddei S, Widmer RJ, Montezano AC, Lüscher TF, et al. Assessment and pathophysiology of microvascular disease: recent progress and clinical implications. Eur Heart J 2021; 42: 2590-604. https://doi.org/10.1093/eurheartj/ehaa857.

[87] Korovesis D, Rubio-Tomás T, Tavernarakis N. Oxidative stress in age-related neurodegenerative diseases: an overview of recent tools and findings. Antioxidants (Basel, Switzerland) 2023; 12: 131. https://doi.org/10.3390/antiox12010131.

[88] Luna-Marco C, Iannantuoni F, Hermo-Argibay A, Devos D, Salazar JD, Víctor VM, et al. Cardiovascular benefits of SGLT2 inhibitors and GLP-1 receptor agonists through effects on mitochondrial function and oxidative stress. Free Radic Biol Med 2024; 213: 19-35. https://doi.org/10.1016/j.freeradbiomed.2024.01.015.

[89] Li F, Mao Z, Du Y, Cui Y, Yang S, Huang K, et al. Mesoporous MOFs with ROS scavenging capacity for the alleviation of inflammation through inhibiting stimulator of interferon genes to promote diabetic wound healing. J Nanobiotechnology 2024; 22: 246. https://doi.org/10.1186/s12951-024-02423-6.

[90] Chang M, Nguyen TT. Strategy for treatment of infected diabetic foot ulcers. Acc Chem Res 2021; 54: 1080-93. https://doi.org/10.1021/acs.accounts.0c00864.

[91] Leal EC, Carvalho E. Heme oxygenase-1 as therapeutic target for diabetic foot ulcers. Int J Mol Sci 2022; 23: 23. https://doi.org/10.3390/ijms231912043.

[92] Xiang J, Shen L, Hong Y. Status and future scope of hydrogels in wound healing: synthesis, materials and evaluation. Eur Polym J 2020; 130: 109609. https://doi.org/10.1016/j.eurpolymj.2020.109609.

[93] Fadilah NIM, Phang SJ, Kamaruzaman N, Salleh A, Zawani M, Sanyal A, et al. Antioxidant biomaterials in cutaneous wound healing and tissue regeneration: a critical review. Antioxidants (Basel, Switzerland) 2023; 12: 787. https://doi.org/10.3390/antiox12040787.

[94] Xie L, Zhang M, Dong B, Guan M, Lu M, Huang Z, et al. Improved refractory wound healing with administration of acidic fibroblast growth factor in diabetic rats. Diabetes Res Clin Pract 2011; 93: 396-403. https://doi.org/10.1016/j.diabres.2011.05.016.

[95] Chukanova EI, Chukanova AS. Alpha-lipoic acid in the treatment of diabetic polyneuropathy. Zhurnal nevrologii i psikhiatrii imeni SS Korsakova 2018; 118: 103-9.

[96] Oyenihi AB, Ayeleso AO, Mukwevho E, Masola B. Antioxidant strategies in the management of diabetic neuropathy. Biomed Res Int 2015; 2015: 1-15. https://doi.org/10.1155/2015/515042.

[97] Zhang J, Chen Q, Zhong J, Liu C, Zheng B, Gong Q. DPP-4 inhibitors as potential candidates for antihypertensive therapy: improving vascular inflammation and assisting the action of traditional antihypertensive drugs. Front Immunol 2019; 10: 1050. https://doi.org/10.3389/fimmu.2019.01050.

[98] Li W, Kandhare AD, Mukherjee AA, Bodhankar SL. Hesperidin, a plant flavonoid accelerated the cutaneous wound healing in streptozotocin-induced diabetic rats: role of TGF-ß/Smads and Ang-1/Tie-2 signaling pathways. EXCLI J 2018; 17: 399-419. https://doi.org/10.17179/excli2018-1036.

[99] Kandhare AD, Ghosh P, Bodhankar SL. Naringin, a flavanone glycoside, promotes angiogenesis and inhibits endothelial apoptosis through modulation of inflammatory and growth factor expression in diabetic foot ulcer in rats. Chem Biol Interact 2014; 219: 101-12. https://doi.org/10.1016/j.cbi.2014.05.012.

[100] Huang YW, Zhu QQ, Yang XY, Xu HH, Sun B, Wang XJ, et al. Wound healing can be improved by (−)-epigallocatechin gallate through targeting notch in streptozotocin-induced diabetic mice. FASEB J 2019; 33: 953-64. https://doi.org/10.1096/fj.201800337R.

[101] Bellini S, Barutta F, Mastrocola R, Imperatore L, Bruno G, Gruden G. Heat shock proteins in vascular diabetic complications: review and future perspective. Int J Mol Sci 2017; 18: 18. https://doi.org/10.3390/ijms18122709.

[102] Nakhjavani M, Morteza A, Khajeali L, Esteghamati A, Khalilzadeh O, Asgarani F, et al. Increased serum HSP70 levels are associated with the duration of diabetes. Cell Stress Chaperones 2010; 15: 959-64. https://doi.org/10.1007/s12192-010-0204-z.

[103] Ishihara T, Suemasu S, Asano T, Tanaka K, Mizushima T. Stimulation of gastric ulcer healing by heat shock protein 70. Biochem Pharmacol 2011; 82: 728-36. https://doi.org/10.1016/j.bcp.2011.06.030.

[104] Ahmed OM, Mohamed T, Moustafa H, Hamdy H, Ahmed RR, Aboud E. Quercetin and low level laser therapy promote wound healing process in diabetic rats via structural reorganization and modulatory effects on inflammation and oxidative stress. Biomed Pharmacother 2018; 101: 58-73. https://doi.org/10.1016/j.biopha.2018.02.040.

[105] Khursheed R, Singh SK, Wadhwa S, Gulati M, Kapoor B, Awasthi A, et al. Opening eyes to therapeutic perspectives of bioactive polyphenols and their nanoformulations against diabetic neuropathy and related complications. Expert Opin Drug Deliv 2021; 18: 427-48. https://doi.org/10.1080/17425247.2021.1846517.

[106] Zheng M, Liu Y, Zhang G, Yang Z, Xu W, Chen Q. The antioxidant properties, metabolism, application and mechanism of ferulic acid in medicine, food, cosmetics, livestock and poultry. Antioxidants (Basel, Switzerland) 2024; 13: 835. https://doi.org/10.3390/antiox13070853.

[107] Emad NA, Pandit J, Ali A, Rathee A, Solanki P, Imtiyaz K, et al. Beeswax-based nanoconstructs enriched dual responsive hydrogel for diabetic foot ulcers in streptozotocin-induced diabetic rats. Int J Biol Macromol 2025; 288: 138500. https://doi.org/10.1016/j.ijbiomac.2024.138500.

[108] Bagdas D, Etoz BC, Gul Z, Ziyanok S, Inan S, Turacozen O, et al. In vivo systemic chlorogenic acid therapy under diabetic conditions: wound healing effects and cytotoxicity/genotoxicity profile. Food Chem Toxicol 2015; 81: 54-61. https://doi.org/10.1016/j.fct.2015.04.001.

[109] Xu C, Qu X. Cerium oxide nanoparticle: a remarkably versatile rare earth nanomaterial for biological applications. NPG Asia Materials 2014; 6: e90-0. https://doi.org/10.1038/am.2013.88.

[110] Zhao H, Huang J, Li Y, Lv X, Zhou H, Wang H, et al. ROS-scavenging hydrogel to promote healing of bacteria infected diabetic wounds. Biomaterials 2020; 258: 120286. https://doi.org/10.1016/j.biomaterials.2020.120286.

[111] Zhang H, Hu H, Dai Y, Xin L, Pang Q, Zhang S, et al. A conductive multifunctional hydrogel dressing with the synergistic effect of ROS-scavenging and electroactivity for the treatment and sensing of chronic diabetic wounds. Acta Biomater 2023; 167: 348-60. https://doi.org/10.1016/j.actbio.2023.05.045.

[112] Afkhamizadeh M, Aboutorabi R, Ravari H, Fathi Najafi M, Ataei Azimi S, Javadian Langaroodi A, et al. Topical propolis improves wound healing in patients with diabetic foot ulcer: a randomized controlled trial. Nat Prod Res 2018; 32: 2096-9. https://doi.org/10.1080/14786419.2017.1363755.

[113] Ashour AM. Propolis attenuates diabetes-induced testicular injury by protecting against DNA damage and suppressing cellular stress. Front Pharmacol 2024; 15: 1416238. https://doi.org/10.3389/fphar.2024.1416238.

[114] Duscher D, Neofytou E, Wong VW, Maan ZN, Rennert RC, Inayathullah M, et al. Transdermal deferoxamine prevents pressure-induced diabetic ulcers. Proc Natl Acad Sci USA 2015; 112: 94-9. https://doi.org/10.1073/pnas.1413445112.

[115] Wang X, Chen X, Zhou W, Men H, Bao T, Sun Y, et al. Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways. Acta Pharm Sin B 2022; 12: 708-22. https://doi.org/10.1016/j.apsb.2021.10.005.

[116] Zayed MA, Wei X, Park KM, Belaygorod L, Naim U, Harvey J, et al. N-Acetylcysteine accelerates amputation stump healing in the setting of diabetes. FASEB J 2017; 31: 2686-95. https://doi.org/10.1096/fj.201601348R.

[117] Qian B, Li J, Guo K, Guo N, Zhong A, Yang J, et al. Antioxidant biocompatible composite collagen dressing for diabetic wound healing in rat model. Regen Biomater 2021; 8: rbab003. https://doi.org/10.1093/rb/rbab003.

[118] Xiong Y, Chen L, Liu P, Yu T, Lin C, Yan C, et al. All-in-one: multifunctional hydrogel accelerates oxidative diabetic wound healing through timed-release of exosome and fibroblast growth factor. Small (Weinheim an der Bergstrasse, Germany) 2022; 18: e2104229. https://doi.org/10.1002/smll.202104229.

[119] Zhao X, Zhang Y, Zuo X, Wang S, Dong X. Knockdown of Adra2a increases secretion of growth factors and wound healing ability in diabetic adipose-derived stem cells. Stem Cells Int 2022; 2022: 1-13. https://doi.org/10.1155/2022/5704628.

[120] Vaidyanathan L. Growth factors in wound healing-a review. Biomed Pharmacol J 2021; 14: 1469-80. https://doi.org/10.13005/bpj/2249.

[121] Maddaluno L, Urwyler C, Werner S. Fibroblast growth factors: key players in regeneration and tissue repair. Development (Cambridge, England) 2017; 144: 4047-60. https://doi.org/10.1242/dev.152587.

[122] Berlanga-Acosta J, Garcia-Ojalvo A, Fernández-Montequin J, Falcon-Cama V, Acosta-Rivero N, Guillen-Nieto G, et al. Epidermal growth factor intralesional delivery in chronic wounds: the Pioneer and standalone technique for reversing wound chronicity and promoting sustainable healing. Int J Mol Sci 2024; 25: 10883. https://doi.org/10.3390/ijms252010883.

[123] Berlangaacosta J, Gavilondo J, del Barco DG, Martín-Machado J, Guillen G. Epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) as tissue healing agents: clarifying concerns about their possible role in malignant transformation and tumor progression. J Carcinog Mutagen 2011; 2: 1. http://dx.doi.org/10.4172/2157-2518.1000115.

[124] Berlanga J, Caballero E, Prats P, López Saura P, Playford RJ. The role of the epidermal growth factor in cell and tissue protection. Medicina Clin 1999; 113: 222-9.

[125] Ishikawa K, Murao A, Aziz M, Wang P. Milk fat globule-epidermal growth factor-VIII-derived oligopeptide 3 (MOP3) attenuates inflammation and improves survival in hepatic ischemia/reperfusion injury. Surgery 2025; 178: 108872. https://doi.org/10.1016/j.surg.2024.09.029.

[126] An Z, Zhang L, Liu Y, Zhao H, Zhang Y, Cao Y, et al. Injectable thioketal-containing hydrogel dressing accelerates skin wound healing with the incorporation of reactive oxygen species scavenging and growth factor release. Biomater Sci 2021; 10: 100-13. https://doi.org/10.1039/d1bm01179k.

[127] Li R, Li DH, Zhang HY, Wang J, Li XK, Xiao J. Growth factors-based therapeutic strategies and their underlying signaling mechanisms for peripheral nerve regeneration. Acta Pharmacol Sin 2020; 41: 1289-300. https://doi.org/10.1038/s41401-019-0338-1.

[128] Shi GJ, Shi GR, Zhou JY, Zhang WJ, Gao CY, Jiang YP, et al. Involvement of growth factors in diabetes mellitus and its complications: a general review. Biomed Pharmacother 2018; 101: 510-27. https://doi.org/10.1016/j.biopha.2018.02.105.

[129] Chen K, Rao Z, Dong S, Chen Y, Wang X, Luo Y, et al. Roles of the fibroblast growth factor signal transduction system in tissue injury repair. Burns Trauma 2022; 10: tkac005. https://doi.org/10.1093/burnst/tkac005.

[130] Liu Y, Liu Y, Deng J, Li W, Nie X. Fibroblast growth factor in diabetic foot ulcer: progress and therapeutic prospects. Front Endocrinol (Lausanne) 2021; 12: 744868. https://doi.org/10.3389/fendo.2021.744868.

[131] Garoufalia Z, Papadopetraki A, Karatza E, Vardakostas D, Philippou A, Kouraklis G, et al. Insulin-like growth factor-I and wound healing, a potential answer to non-healing wounds: a systematic review of the literature and future perspectives. Biomed Rep 2021; 15: 66. https://doi.org/10.3892/br.2021.1442.

[132] Chen HH, Fu FS, Chen QW, Zhang Y, Zhang XZ. Two-pronged microbe delivery of nitric oxide and oxygen for diabetic wound healing. Nano Lett 2023; 23: 5595-602. https://doi.org/10.1021/acs.nanolett.3c01023.

[133] Baicus C, Purcarea A, von Elm E, Delcea C, Furtunescu FL. Alpha-lipoic acid for diabetic peripheral neuropathy. Cochrane Database Syst Rev 2024; 2024: Cd012967. https://doi.org/10.1002/14651858.CD012967.pub2.

[134] Lin Q, Li K, Chen Y, Xie J, Wu C, Cui C, et al. Oxidative stress in diabetic peripheral neuropathy: pathway and mechanism-based treatment. Mol Neurobiol 2023; 60: 4574-94. https://doi.org/10.1007/s12035-023-03342-7.

[135] Yarahmadi A, Saeed Modaghegh MH, Mostafavi-Pour Z, Azarpira N, Mousavian A, Bonakdaran S, et al. The effect of platelet-rich plasma-fibrin glue dressing in combination with oral vitamin E and C for treatment of non-healing diabetic foot ulcers: a randomized, double-blind, parallel-group, clinical trial. Expert Opin Biol Ther 2021; 21: 687-96. https://doi.org/10.1080/14712598.2021.1897100.

[136] Li K, Chen Y, Xie J, Cai W, Pang C, Cui C, et al. How vitamins act as novel agents for ameliorating diabetic peripheral neuropathy: a comprehensive overview. Ageing Res Rev 2023; 91: 102064. https://doi.org/10.1016/j.arr.2023.102064.

[137] Kuthati Y, Rao VN, Busa P, Wong CS. Teneligliptin exerts antinociceptive effects in rat model of partial sciatic nerve transection induced neuropathic pain. Antioxidants (Basel, Switzerland) 2021; 10: 1438. https://doi.org/10.3390/antiox10091438.

[138] Li R, Zeng X, Yang M, Xu X, Feng J, Bao L, et al. Antidiabetic agent DPP-4i facilitates murine breast cancer metastasis by oncogenic ROS-NRF2-HO-1 Axis via a positive NRF2-HO-1 feedback loop. Front Oncol 2021; 11: 679816. https://doi.org/10.3389/fonc.2021.679816.

[139] Lin Y, Wei Y, Wei Y, Yu H, Zhang W, Li C, et al. Dexmedetomidine alleviates oxidative stress and mitochondrial dysfunction in diabetic peripheral neuropathy via the microRNA-34a/SIRT2/S1PR1 axis. Int Immunopharmacol 2023; 117: 109910. https://doi.org/10.1016/j.intimp.2023.109910.

[140] Abdelkader NF, Ibrahim SM, Moustafa PE, Elbaset MA. Inosine mitigated diabetic peripheral neuropathy via modulating GLO1/AGEs/RAGE/NF-κB/Nrf2 and TGF-β/PKC/TRPV1 signaling pathways. Biomed Pharmacother 2022; 145: 112395. https://doi.org/10.1016/j.biopha.2021.112395.

[141] Ramirez-Acuña JM, Cardenas-Cadena SA, Marquez-Salas PA, Garza-Veloz I, Perez-Favila A, Cid-Baez MA, et al. Diabetic foot ulcers: current advances in antimicrobial therapies and emerging treatments. Antibiotics (Basel, Switzerland) 2019; 8: 193. https://doi.org/10.3390/antibiotics8040193.

[142] Wright A, Wood S, De Silva J, Bell JS. Systemic antimicrobial therapy for diabetic foot infections: An overview of systematic reviews. Antibiotics (Basel, Switzerland) 2023; 12: 1041. https://doi.org/10.3390/antibiotics12061041.

[143] Kawasuji H, Nagaoka K, Tsuji Y, Kimoto K, Takegoshi Y, Kaneda M, et al. Effectiveness and safety of linezolid versus vancomycin, Teicoplanin, or Daptomycin against methicillin-resistant Staphylococcus aureus bacteremia: a systematic review and meta-analysis. Antibiotics (Basel, Switzerland) 2023; 12: 697. https://doi.org/10.3390/antibiotics12040697.

[144] Guo X, Luo W, Wu L, Zhang L, Chen Y, Li T, et al. Natural products from herbal medicine self-assemble into advanced bioactive materials. Adv Sci (Weinh) 2024; 11: e2403388. https://doi.org/10.1002/advs.202403388.

[145] Yu WH, Zhang T, Xu H. Role of dipeptidyl dipeptidase 4 inhibitors in the management of diabetic foot. Int J Low Extrem Wounds 2024; 23: 577-84. https://doi.org/10.1177/15347346221082776.

[146] Xiao F, Rui S, Zhang X, Ma Y, Wu X, Hao W, et al. Accelerating diabetic wound healing with Ramulus Mori (Sangzhi) alkaloids via NRF2/HO-1/eNOS pathway. Phytomedicine 2024; 134: 155990. https://doi.org/10.1016/j.phymed.2024.155990.

[147] Zhou X, Guo Y, Yang K, Liu P, Wang J. The signaling pathways of traditional Chinese medicine in promoting diabetic wound healing. J Ethnopharmacol 2022; 282: 114662. https://doi.org/10.1016/j.jep.2021.114662.

[148] Liu Y, Yang X, Liu Y, Jiang T, Ren S, Chen J, et al. NRF2 signalling pathway: new insights and progress in the field of wound healing. J Cell Mol Med 2021; 25: 5857-68. https://doi.org/10.1111/jcmm.16597.

[149] Ning Y, Yuan Z, Wang Q, He J, Zhu W, Ren DN, et al. Epigallocatechin-3-gallate promotes wound healing response in diabetic mice by activating keratinocytes and promoting re-epithelialization. Phytotherapy Res 2024; 38: 1013-27. https://doi.org/10.1002/ptr.8099.

[150] Zhang J, Zhou R, Xiang C, Jia Q, Wu H, Yang H. Huangbai liniment accelerated wound healing by activating Nrf2 signaling in diabetes. Oxidative Med Cell Longev 2020; 2020: 1-20. https://doi.org/10.1155/2020/4951820.

[151] Tytell M, Hooper PL. Heat shock proteins: new keys to the development of cytoprotective therapies. Expert Opin Ther Targets 2001; 5: 267-87. https://doi.org/10.1517/14728222.5.2.267.

[152] Hu C, Yang J, Qi Z, Wu H, Wang B, Zou F, et al. Heat shock proteins: biological functions, pathological roles, and therapeutic opportunities. MedComm 2022; 3: e161. https://doi.org/10.1002/mco2.161.

[153] Li Y, Yu Y, Li Y, Wang H, Li Q. Molecular evolution of the heat shock protein family and the role of HSP30 in immune response and wound healing in lampreys (Lethenteron reissneri). Fish Shellfish Immunol 2024; 145: 109323. https://doi.org/10.1016/j.fsi.2023.109323.

[154] Shan R, Liu N, Yan Y, Liu B. Apoptosis, autophagy and atherosclerosis: relationships and the role of Hsp27. Pharmacol Res 2021; 166: 105169. https://doi.org/10.1016/j.phrs.2020.105169.

[155] Huang D, Tian C, Sun Z, Niu J, Wang G. Potential synergistic regulation of hsp70 and antioxidant enzyme genes in Pyropia yezoensis under high temperature stress. Algal Res 2024; 78: 103375. https://doi.org/10.1016/j.algal.2023.103375.

[156] Stachura A, Khanna I, Krysiak P, Paskal W, Włodarski P. Wound healing impairment in type 2 diabetes model of leptin-deficient mice-a mechanistic systematic review. Int J Mol Sci 2022; 23: 8621. https://doi.org/10.3390/ijms23158621.

[157] Alagar Boopathy LR, Jacob-Tomas S, Alecki C, Vera M. Mechanisms tailoring the expression of heat shock proteins to proteostasis challenges. J Biol Chem 2022; 298: 101796. https://doi.org/10.1016/j.jbc.2022.101796.

[158] Hu M, Jiang W, Ye C, Hu T, Yu Q, Meng M, et al. Honokiol attenuates high glucose-induced peripheral neuropathy via inhibiting ferroptosis and activating AMPK/SIRT1/PGC-1α pathway in Schwann cells. Phytother Res 2023; 37: 5787-802. https://doi.org/10.1002/ptr.7984.

[159] Liu Y, Xia G, Chen Y, Xia H, Xu J, Guo L, et al. Purpurolide C-based microneedle promotes macrophage-mediated diabetic wound healing via inhibiting TLR4-MD2 dimerization and MYD88 phosphorylation. Acta Pharm Sin B 2023; 13: 5060-73. https://doi.org/10.1016/j.apsb.2023.05.032.

[160] Ao L, Chen Z, Yin J, Leng Y, Luo Y, Fu X, et al. Chinese herbal medicine and active ingredients for diabetic cardiomyopathy: molecular mechanisms regulating endoplasmic reticulum stress. Front Pharmacol 2023; 14: 1290023. https://doi.org/10.3389/fphar.2023.1290023.

[161] Vellayappan MV, Jaganathan SK, Manikandan A. Nanomaterials as a game changer in the management and treatment of diabetic foot ulcers. RSC Adv 2016; 6: 114859-78. https://doi.org/10.1039/C6RA24590K.

[162] Fifere A, Moleavin I-AT, Lungoci A-L, Marangoci NL, Pinteala M. Inorganic Nanoparticles as Free Radical Scavengers. In Abadie MJM, Pinteala M, Rotaru A (eds). New Trends in Macromolecular and Supramolecular Chemistry for Biological Applications. Cham: Springer International Publishing, 2021. 295-329.

[163] Hosseinzadeh A, Zamani A, Johari HG, Vaez A, Golchin A, Tayebi L, et al. Moving beyond nanotechnology to uncover a glimmer of hope in diabetes medicine: effective nanoparticle-based therapeutic strategies for the management and treatment of diabetic foot ulcers. Cell Biochem Funct 2023; 41: 517-41. https://doi.org/10.1002/cbf.3816.

[164] DiSanto RM, Subramanian V, Gu Z. Recent advances in nanotechnology for diabetes treatment. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2015; 7: 548-64. https://doi.org/10.1002/wnan.1329.

[165] Rui S, Dai L, Zhang X, He M, Xu F, Wu W, et al. Exosomal miRNA-26b-5p from PRP suppresses NETs by targeting MMP-8 to promote diabetic wound healing. J Control Release 2024; 372: 221-33. https://doi.org/10.1016/j.jconrel.2024.06.050.

[166] Xie H, Xie XH, Hu GX, Prabhakaran V, Saha S, Gonzalez-Lopez L, et al. Ta-TiOx nanoparticles as radical scavengers to improve the durability of Fe-N-C oxygen reduction catalysts. Nat Energy 2022; 7: 281-9. https://doi.org/10.1038/s41560-022-00988-w.

[167] Zhang F, Chan SW, Spanier JE, Apak E, Jin Q, Robinson RD, et al. Cerium oxide nanoparticles: size-selective formation and structure analysis. Appl Phys Lett 2002; 80: 127-9. https://doi.org/10.1063/1.1430502.

[168] Sheng HC, Yin TY, Xiao BB, Jiang XB. Modeling the lattice expansion and contraction of nanocrystals in different interface environments. J Nanopart Res 2022; 24: 9.

[169] Tsai YY, Oca-Cossio J, Agering K, Simpson NE, Atkinson MA, Wasserfall CH, et al. Novel synthesis of cerium oxide nanoparticles for free radical scavenging. Nanomedicine 2007; 2: 325-32. https://doi.org/10.2217/17435889.2.3.325.

[170] Robinson RD, Spanier JE, Zhang F, Chan SW, Herman IP. Visible thermal emission from sub-band-gap laser excited cerium dioxide particles. J Appl Phys 2002; 92: 1936-41. https://doi.org/10.1063/1.1494130.

[171] Lai CM, Chen WJ, Qin Y, Xu D, Lai YK, He SH. Innovative hydrogel design: tailoring immunomodulation for optimal chronic wound recovery. Adv Sci (Weinh) 2025; 12: 2412360. https://doi.org/10.1002/advs.202412360.

[172] Utara S, Hunpratub S, Pinitsoontorn S, Phokha S. Characterization and magnetic performance of pure CeO2 nanoparticles via an ozonolysis reaction. Results Phys 2021; 30: 104890. https://doi.org/10.1016/j.rinp.2021.104890.

[173] Zhou L, Xie M, Rao C, Su H, Pang Y, Lou H, et al. Oxygen vacancies induced by Ce3+/Ce4+ doping mediate the formation of Bi0/Bi2O3/Bi2O2.75 nanosheets for visible light-driven photocatalytic degradation of lignin. Chem Eng J 2023; 471: 144574. https://doi.org/10.1016/j.cej.2023.144574.

[174] Chakravarthy Y, Bhandari S, Chaturvedi V, Pragatheeswaran A, Nagraj A, Thiyagarajan TK, et al. Plasma spray deposition of yttrium oxide on graphite, coating characterization and interaction with molten uranium. J Eur Ceram Soc 2015; 35: 787-94. https://doi.org/10.1016/j.jeurceramsoc.2014.09.012.

[175] Rajakumar G, Mao LB, Bao T, Wen W, Wang SF, Gomathi T, et al. Yttrium oxide nanoparticle synthesis: an overview of methods of preparation and biomedical applications. Appl Sci-Basel 2021; 11: 24.

[176] Song X, Shang P, Sun ZW, Lu MZ, You GX, Yan SD, et al. Therapeutic effect of yttrium oxide nanoparticles for the treatment of fulminant hepatic failure. Nanomedicine 2019; 14: 2519-33. https://doi.org/10.2217/nnm-2019-0154.

[177] Yadav N. Cerium oxide nanostructures: properties, biomedical applications and surface coatings. 3 Biotech 2022; 12: 20. https://doi.org/10.1007/s13205-022-03186-3.

[178] Wu C, Mao J, Wang X, Yang R, Wang C, Li C, et al. Advances in treatment strategies based on scavenging reactive oxygen species of nanoparticles for atherosclerosis. J Nanobiotechnology 2023; 21: 271. https://doi.org/10.1186/s12951-023-02058-z.

[179] Joorabloo A, Liu T. Recent advances in reactive oxygen species scavenging nanomaterials for wound healing. Exploration (Beijing, China) 2024; 4: 20230066. https://doi.org/10.1002/EXP.20230066.

[180] Pormohammad A, Firrincieli A, Salazar-Alemán DA, Mohammadi M, Hansen D, Cappelletti M, et al. Insights into the synergistic antibacterial activity of silver nitrate with potassium tellurite against Pseudomonas aeruginosa. Microbiology Spectr 2023; 11: e0062823. https://doi.org/10.1128/spectrum.00628-23.

[181] Li R, Mao J, Zheng P, Wang R, Yang Z, Qian S. Improving the biocompatibility and antibacterial efficacy of silver nanoparticles functionalized with (LLRR)(3) antimicrobial peptide. World J Microbiol Biotechnol 2023; 40: 1. https://doi.org/10.1007/s11274-023-03792-0.

[182] Paul S, Sarkar I, Sarkar N, Bose A, Chakraborty M, Chakraborty A, et al. Silver nanoparticles in diabetes mellitus: therapeutic potential and mechanistic insights. Bull Natl Res Cent 2024; 48: 33. https://doi.org/10.1186/s42269-024-01182-6.

[183] Choudhury H, Pandey M, Lim YQ, Low CY, Lee CT, Marilyn TCL, et al. Silver nanoparticles: advanced and promising technology in diabetic wound therapy. Mater Sci Eng C-Mater Biol Appl 2020; 112: 16.

[184] Wang W, Lu KJ, Yu CH, Huang QL, Du YZ. Nano-drug delivery systems in wound treatment and skin regeneration. J Nanobiotechnol 2019; 17: 82. https://doi.org/10.1186/s12951-019-0514-y.

[185] Sibuyi NRS, Moabelo KL, Fadaka AO, Meyer S, Onani MO, Madiehe AM, et al. Multifunctional gold nanoparticles for improved diagnostic and therapeutic applications: a review. Nanoscale Res Lett 2021; 16: 174. https://doi.org/10.1186/s11671-021-03632-w.

[186] Lee KX, Shameli K, Yew YP, Teow SY, Jahangirian H, Rafiee-Moghaddam R, et al. Recent developments in the facile biosynthesis of gold nanoparticles (AuNPs) and their biomedical applications. Int J Nanomedicine 2020; 15: 275-300. https://doi.org/10.2147/IJN.S233789.

[187] BarathManiKanth S, Kalishwaralal K, Sriram M, Pandian SRK, Youn H-s, Eom S, et al. Anti-oxidant effect of gold nanoparticles restrains hyperglycemic conditions in diabetic mice. J Nanobiotechnol 2010; 8: 8. https://doi.org/10.1186/1477-3155-8-16.

[188] Yadav S, Prakash A, Yadav U, Saxena PS, Srivastava A. A review on advanced nanoengineered biomaterials for chronic wound healing. Proc Indian Natl Sci Acad 2023; 89: 470-82. https://doi.org/10.1007/s43538-023-00183-9.

[189] Veiseh O, Tang BC, Whitehead KA, Anderson DG, Langer R. Managing diabetes with nanomedicine: challenges and opportunities. Nat Rev Drug Discov 2014; 14: 45-57. https://doi.org/10.1038/nrd4477.

[190] Huang X, He D, Pan Z, Luo G, Deng J. Reactive-oxygen-species-scavenging nanomaterials for resolving inflammation. Mater Today Bio 2021; 11: 100124. https://doi.org/10.1016/j.mtbio.2021.100124.

[191] Cao H, Duan L, Zhang Y, Cao J, Zhang K. Current hydrogel advances in physicochemical and biological response-driven biomedical application diversity. Signal Transduct Target Ther 2021; 6: 426. https://doi.org/10.1038/s41392-021-00830-x.

[192] Xu Z, Liu Y, Ma R, Chen J, Qiu J, Du S, et al. Thermosensitive hydrogel incorporating Prussian blue nanoparticles promotes diabetic wound healing via ROS scavenging and mitochondrial function restoration. ACS Appl Mater Interfaces 2022; 14: 14059-71. https://doi.org/10.1021/acsami.1c24569.

[193] Zhou S, Cai H, He X, Tang Z, Lu S. Enzyme-mimetic antioxidant nanomaterials for ROS scavenging: design, classification, and biological applications. Coord Chem Rev 2024; 500: 215536. https://doi.org/10.1016/j.ccr.2023.215536.

[194] Fan R, Cheng Y, Wang R, Zhang T, Zhang H, Li J, et al. Thermosensitive hydrogels and advances in their application in disease therapy. Polymers 2022; 14: 2379. https://doi.org/10.3390/polym14122379.

[195] Karas RA, Alexeree S, Elsayed H, Attia YA. Assessment of wound healing activity in diabetic mice treated with a novel therapeutic combination of selenium nanoparticles and platelets rich plasma. Sci Rep 2024; 14: 5346. https://doi.org/10.1038/s41598-024-54064-2.

[196] Verdolino DV, Thomason HA, Fotticchia A, Cartmell S. Wound dressings: curbing inflammation in chronic wound healing. Emerg Top Life Sci 2021; 5: 523-37. https://doi.org/10.1042/ETLS20200346.

[197] Yang LL, Liang FT, Zhang XF, Jiang YD, Duan F, Li LR, et al. Remodeling microenvironment based on MOFs-hydrogel hybrid system for improving diabetic wound healing. Chem Eng J 2022; 427: 131506. https://doi.org/10.1016/j.cej.2021.131506.

[198] Li X, Ye X, Qi J, Fan R, Gao X, Wu Y, et al. EGF and curcumin co-encapsulated nanoparticle/hydrogel system as potent skin regeneration agent. Int J Nanomedicine 2016; 11: 3993-4009. https://doi.org/10.2147/IJN.S104350.

[199] Zhang S, Wang L, Kang Y, Wu J, Zhang Z. Nanomaterial-based reactive oxygen species scavengers for osteoarthritis therapy. Acta Biomater 2023; 162: 1-19. https://doi.org/10.1016/j.actbio.2023.03.030.

[200] Wang Y, Yan J, Wen N, Xiong H, Cai S, He Q, et al. Metal-organic frameworks for stimuli-responsive drug delivery. Biomaterials 2020; 230: 119619. https://doi.org/10.1016/j.biomaterials.2019.119619.

[201] Li X, Bai L, Zhang X, Fang Q, Chen G, Xu G. Application of Bletilla striata polysaccharide hydrogel for wound healing among in diabetes. Colloids Surf B: Biointerfaces 2024; 241: 114033. https://doi.org/10.1016/j.colsurfb.2024.114033.

[202] Hu B, Ouyang Y, Zhao T, Wang Z, Yan Q, Qian Q, et al. Antioxidant hydrogels: antioxidant mechanisms, design strategies, and applications in the treatment of oxidative stress-related diseases antioxidant hydrogels: antioxidant mechanisms, design strategies, and applications in the treatment of oxidative stress-related diseases. Adv Healthc Mater 2024; 13: 2303817. https://doi.org/10.1002/adhm.202303817.

[203] Shi S, Wang L, Song C, Yao L, Xiao J. Recent progresses of collagen dressings for chronic skin wound healing. Collagen Leather 2023; 5: 31. https://doi.org/10.1186/s42825-023-00136-4.

[204] Jiao Y, Chen X, Niu Y, Huang S, Wang J, Luo M, et al. Wharton’s jelly mesenchymal stem cells embedded in PF-127 hydrogel plus sodium ascorbyl phosphate combination promote diabetic wound healing in type 2 diabetic rat. Stem Cell Res Ther 2021; 12: 559. https://doi.org/10.1186/s13287-021-02626-w.

[205] Li S, Yang C, Li J, Zhang C, Zhu L, Song Y, et al. Progress in Pluronic F127 derivatives for application in wound healing and repair. Int J Nanomedicine 2023; 18: 4485-505. https://doi.org/10.2147/IJN.S418534.

[206] Deng Q, Huang S, Wen J, Jiao Y, Su X, Shi G, et al. PF-127 hydrogel plus sodium ascorbyl phosphate improves Wharton’s jelly mesenchymal stem cell-mediated skin wound healing in mice. Stem Cell Res Ther 2020; 11: 143. https://doi.org/10.1186/s13287-020-01638-2.

[207] Chen R, Wang P, Xie J, Tang Z, Fu J, Ning Y, et al. A multifunctional injectable, self-healing, and adhesive hydrogel-based wound dressing stimulated diabetic wound healing with combined reactive oxygen species scavenging, hyperglycemia reducing, and bacteria-killing abilities. J Nanobiotechnol 2024; 22: 444. https://doi.org/10.1186/s12951-024-02687-y.

[208] Lanir Y.Multi-scale structural modeling of soft tissues mechanics and mechanobiology. J Elast 2017; 129: 7-48. https://doi.org/10.1007/s10659-016-9607-0.

[209] Kumar M, Kumar D, Kumar D, Garg Y, Chopra S, Bhatia A. Therapeutic potential of nanocarrier mediated delivery of peptides for wound healing: current status, challenges and future prospective. AAPS PharmSciTech 2024; 25: 108. https://doi.org/10.1208/s12249-024-02827-5.

[210] Cui Z, Huang B, Zheng J, Tian J, Zhang W. A TME-enlightened protein-binding photodynamic nanoinhibitor for highly effective oncology treatment. Proc Natl Acad Sci USA 2024; 121: e2321545121. https://doi.org/10.1073/pnas.2321545121.

[211] Lansdown AB. Physiological and toxicological changes in the skin resulting from the action and interaction of metal ions. Crit Rev Toxicol 1995; 25: 397-462. https://doi.org/10.3109/10408449509049339.

[212] Crane JK. Metal nanoparticles in infection and immunity. Immunol Investig 2020; 49: 794-807. https://doi.org/10.1080/08820139.2020.1776724.

[213] Birk SE, Boisen A, Nielsen LH. Polymeric nano-and microparticulate drug delivery systems for treatment of biofilms. Adv Drug Deliv Rev 2021; 174: 30-52. https://doi.org/10.1016/j.addr.2021.04.005.

[214] Luan Q, Qiao R, Wu X, Shan J, Song C, Zhao X, et al. Plant-derived Chinese herbal hydrogel microneedle patches for wound healing. Small (Weinheim an der Bergstrasse, Germany) 2024; 20: e2404850. https://doi.org/10.1002/smll.202404850.

[215] Li T, Zhang L, Qu X, Lei B. Advanced thermoactive nanomaterials for thermomedical tissue regeneration: opportunities and challenges. Small Methods 2024; 9: e2400510. https://doi.org/10.1002/smtd.202400510.

[216] Vendidandala NR, Yin TP, Nelli G, Pasupuleti VR, Nyamathulla S, Mokhtar SI. Gallocatechin-silver nanoparticle impregnated cotton gauze patches enhance wound healing in diabetic rats by suppressing oxidative stress and inflammation via modulating the Nrf2/HO-1 and TLR4/NF-κB pathways. Life Sci 2021; 286: 120019. https://doi.org/10.1016/j.lfs.2021.120019.

[217] Soltanzadeh M, Peighambardoust SH, Ghanbarzadeh B, Mohammadi M, Lorenzo JM. Chitosan nanoparticles encapsulating lemongrass (Cymbopogon commutatus) essential oil: physicochemical, structural, antimicrobial and in-vitro release properties. Int J Biol Macromol 2021; 192: 1084-97. https://doi.org/10.1016/j.ijbiomac.2021.10.070.

[218] Ramalingam R, Dhand C, Mayandi V, Leung CM, Ezhilarasu H, Karuppannan SK, et al. Core-Shell structured antimicrobial nanofiber dressings containing herbal extract and antibiotics combination for the prevention of biofilms and promotion of cutaneous wound healing. ACS Appl Mater Interfaces 2021; 13: 24356-69. https://doi.org/10.1021/acsami.0c20642.

[219] Carvalho APG, Alegria E, Fantoni A, Ferraria AM, do Rego AMB, Ribeiro APC. Effect of graphene vs. reduced graphene oxide in gold nanoparticles for optical biosensors-a comparative study. Biosensors 2022; 12: 163. https://doi.org/10.3390/bios12030163.

[220] Sumana M, Thirumurugan A, Muthukumaran P, Anand K. Biodegradable natural polymeric nanoparticles as carrier for drug delivery. J I N f N T 2020; 1: 231-46. https://doi.org/10.1007/978-3-030-36260-7_8.

[221] Gavas S, Quazi S, Karpiński TM. Nanoparticles for cancer therapy: current progress and challenges. Nanoscale Res Lett 2021; 16: 173. https://doi.org/10.1186/s11671-021-03628-6.

[222] Xiao X, Zhao F, DuBois DB, Liu Q, Zhang YL, Yao Q, et al. Nanozymes for the therapeutic treatment of diabetic foot ulcers. ACS Biomater Sci Eng 2024; 10: 4195-226. https://doi.org/10.1021/acsbiomaterials.4c00470.

[223] Bhairam M, Dubey N, Pandey RK, Shukla SS, Gidwani B. Nanobiomaterials: A Site-Targeted Approach to Antidiabetic Drug Delivery. In Pradhan M, Yadav K, Singh Chauhan N (eds). Biomaterial-Inspired Nanomedicines for Targeted Therapies. Singapore: Springer Nature Singapore, 2024. 237-75.

[224] Dai L, Liu J, Yang T, Yu X, Lu Y, Pan L, et al. Lipoic acid-boronophenylalanine-derived multifunctional vesicles for cancer chemoradiotherapy. Nat Commun 2025; 16: 1329. https://doi.org/10.1038/s41467-025-56507-4.