Bioengineered Nanozymes for Orthopedic Degenerative Diseases: From Catalytic Mechanisms to Multimodal Therapy

Abstract

Orthopedic degenerative diseases, particularly osteoarthritis (OA) and intervertebral disc degeneration (IDD), represent a growing global health crisis. Current clinical management relying on analgesics and anti-inflammatory drugs provides only symptomatic relief, while surgical interventions, though temporarily effective for advanced cases, carry inherent risks of adjacent segment degeneration and surgical complications. Synthetic nanozymes, which possess intrinsic anti-inflammatory and antioxidant properties, demonstrate significant therapeutic advantages in the treatment of orthopedic degenerative diseases. This review summarizes recent advances in nanonzyme-based therapeutics, with a focus on their regulatory roles in mitigating orthopedic degenerative diseases, particularly IDD and OA. Key mechanisms include anti-inflammatory effects, extracellular matrix remodeling, attenuation of cellular senescence and death, and antioxidative stress activities. We systematically analyze nanonzymes categorized by their diverse enzymatic activities and chemical compositions. Furthermore, we explore emerging combinatorial strategies employing nanonzyme delivery systems to achieve synergistic therapeutic outcomes and enhanced efficacy. The comprehensive discussion highlights the transformative potential of nanonzymes in advancing IDD and OA treatment paradigms, offering novel perspectives for future research and clinical applications.

Keywords

cell death / extracellular matrix degradation / inflammation / nanomaterial / orthopedic degenerative diseases / oxidative stress

References

[1] W. Guo, B. L. Li, J. Y. Zhao, X. M. Li, and L. F. Wang, “Causal Associations Between Modifiable Risk Factors and Intervertebral Disc Degeneration,” Spine Journal 24, no. 2 (2024): 195–209.

[2] E. R. Vina and C. K. Kwoh, “Epidemiology of Osteoarthritis: Literature Update,” Current Opinion in Rheumatology 30, no. 2 (2018): 160–167.

[3] S. K. Mirza and R. A. Deyo, “Systematic Review of Randomized Trials Comparing Lumbar Fusion Surgery to Nonoperative Care for Treatment of Chronic Back Pain,” Spine 32, no. 7 (2007): 816–823.

[4] D. Sheyn, S. Ben-David, W. Tawackoli, et al., “Human iPSCs Can Be Differentiated Into Notochordal Cells That Reduce Intervertebral Disc Degeneration in a Porcine Model,” Theranostics 9, no. 25 (2019): 7506–7524.

[5] Z. Liao, R. Luo, G. Li, et al., “Exosomes From Mesenchymal Stem Cells Modulate Endoplasmic Reticulum Stress to Protect Against Nucleus Pulposus Cell Death and Ameliorate Intervertebral Disc Degeneration In Vivo,” Theranostics 9, no. 14 (2019): 4084–4100.

[6] S. Koo, H. S. Sohn, T. H. Kim, et al., “Ceria-Vesicle Nanohybrid Therapeutic for Modulation of Innate and Adaptive Immunity in a Collagen-Induced Arthritis Model,” Nature Nanotechnology 18, no. 12 (2023): 1502–1514.

[7] S. Zhao, D. Wang, Q. Zhou, et al., “Nanozyme-Based Inulin@Nanogold for Adhesive and Antibacterial Agent With Enhanced Biosafety,” International Journal of Biological Macromolecules 262, no. Pt 2 (2024): 129207.

[8] H. Wang, X. Liu, X. Yan, et al., “An ATPase-Mimicking MXene Nanozyme Pharmacologically Breaks the Ironclad Defense System for Ferroptosis Cancer Therapy,” Biomaterials 307 (2024): 122523.

[9] W. Xu, X. Cai, Y. Wu, et al., “Biomimetic Single Al-OH Site With High Acetylcholinesterase-Like Activity and Self-Defense Ability for Neuroprotection,” Nature Communications 14, no. 1 (2023): 6064.

[10] L. Zhang, A. Song, Q. C. Yang, et al., “Integration of AIEgens Into Covalent Organic Frameworks for Pyroptosis and Ferroptosis Primed Cancer Immunotherapy,” Nature Communications 14, no. 1 (2023): 5355.

[11] D. Chen, Z. Xia, Z. Guo, et al., “Bioinspired Porous Three-Coordinated Single-Atom Fe Nanozyme With Oxidase-Like Activity for Tumor Visual Identification via Glutathione,” Nature Communications 14, no. 1 (2023): 7127.

[12] D. Jiang, D. Ni, Z. T. Rosenkrans, P. Huang, X. Yan, and W. Cai, “Nanozyme: New Horizons for Responsive Biomedical Applications,” Chemical Society Reviews 48, no. 14 (2019): 3683–3704.

[13] Y. Huang, J. Ren, and X. Qu, “Nanozymes: Classification, Catalytic Mechanisms, Activity Regulation, and Applications,” Chemical Reviews 119, no. 6 (2019): 4357–4412.

[14] J. Dowdell, M. Erwin, T. Choma, A. Vaccaro, J. Iatridis, and S. K. Cho, “Intervertebral Disk Degeneration and Repair,” Neurosurgery 80, no. 3S (2017): S46–S54.

[15] S. Ohtori, G. Inoue, M. Miyagi, and K. Takahashi, “Pathomechanisms of Discogenic Low Back Pain in Humans and Animal Models,” Spine Journal 15, no. 6 (2015): 1347–1355.

[16] W. C. W. Chan, K. L. Sze, D. Samartzis, V. Y. L. Leung, and D. Chan, “Structure and Biology of the Intervertebral Disk in Health and Disease,” Orthopedic Clinics of North America 42, no. 4 (2011): 447–464.

[17] T. Oichi, Y. Taniguchi, Y. Oshima, S. Tanaka, and T. Saito, “Pathomechanism of Intervertebral Disc Degeneration,” JOR Spine 3, no. 1 (2020): e1076.

[18] G. Fontana, E. See, and A. Pandit, “Current Trends in Biologics Delivery to Restore Intervertebral Disc Anabolism,” Advanced Drug Delivery Reviews 84 (2015): 146–158.

[19] M. McCann and C. Séguin, “Notochord Cells in Intervertebral Disc Development and Degeneration,” Journal of Developmental Biology 4, no. 1 (2016): 3.

[20] G. Lang, Y. Liu, J. Geries, et al., “An Intervertebral Disc Whole Organ Culture System to Investigate Proinflammatory and Degenerative Disc Disease Condition,” Journal of Tissue Engineering and Regenerative Medicine 12, no. 4 (2018): e2051–e2061.

[21] L. Mao, W. Wu, M. Wang, et al., “Targeted Treatment for Osteoarthritis: Drugs and Delivery System,” Drug Delivery 28, no. 1 (2021): 1861–1876.

[22] X. Ren, D. Chen, Y. Wang, et al., “Nanozymes-Recent Development and Biomedical Applications,” Journal of Nanobiotechnology 20, no. 1 (2022): 92.

[23] H. Wei and E. Wang, “Nanomaterials With Enzyme-Like Characteristics (Nanozymes): Next-Generation Artificial Enzymes,” Chemical Society Reviews 42, no. 14 (2013): 6060–6093.

[24] M. Goldring, M. Otero, D. Plumb, et al., “Roles of Inflammatory and Anabolic Cytokines in Cartilage Metabolism: Signals and Multiple Effectors Converge Upon MMP-13 Regulation in Osteoarthritis,” European Cells and Materials 21 (2011): 202–220.

[25] J. I. Pulai, H. Chen, H. J. Im, et al., “NF-κB Mediates the Stimulation of Cytokine and Chemokine Expression by Human Articular Chondrocytes in Response to Fibronectin Fragments,” Journal of Immunology 174, no. 9 (2005): 5781–5788.

[26] C. L. Le Maitre, A. J. Freemont, and J. A. Hoyland, “Accelerated Cellular Senescence in Degenerate Intervertebral Discs: A Possible Role in the Pathogenesis of Intervertebral Disc Degeneration,” Arthritis Research & Therapy 9, no. 3 (2007): R45.

[27] N. Fine, S. Lively, C. A. Séguin, A. V. Perruccio, M. Kapoor, and R. Rampersaud, “Intervertebral Disc Degeneration and Osteoarthritis: A Common Molecular Disease Spectrum,” Nature Reviews Rheumatology 19, no. 3 (2023): 136–152.

[28] P. B. Medawar, “Immunity to Homologous Grafted Skin; The Fate of Skin Homografts Transplanted to the Brain, to Subcutaneous Tissue, and to the Anterior Chamber of the Eye,” British Journal of Experimental Pathology 29, no. 1 (1948): 58–69.

[29] J. B. Park, H. Chang, and K. W. Kim, “Expression of Fas Ligand and Apoptosis of Disc Cells in Herniated Lumbar Disc Tissue,” Spine 26, no. 6 (2001): 618–621.

[30] P. Patil, Q. Dong, D. Wang, et al., “Systemic Clearance of p16(INK4a)-Positive Senescent cells Mitigates Age-Associated Intervertebral Disc Degeneration,” Aging cell 18, no. 3 (2019): e12927.

[31] D. Wang, Q. Shang, J. Mao, et al., “Phosphorylation of KRT8 (Keratin 8) by Excessive Mechanical Load-Activated PKN (Protein Kinase N) Impairs Autophagosome Initiation and Contributes to Disc Degeneration,” Autophagy 19, no. 9 (2023): 2485–2503.

[32] L. Salzberg, “The Physiology of Low Back Pain,” Primary Care: Clinics in Office Practice 39, no. 3 (2012): 487–498.

[33] K. Singh, K. Masuda, and H. S. An, “Animal Models for Human Disc Degeneration,” Spine Journal 5, no. 6 Suppl (2005): S267–S279.

[34] M. F. Shamji, L. A. Setton, W. Jarvis, et al., “Proinflammatory Cytokine Expression Profile in Degenerated and Herniated Human Intervertebral Disc Tissues,” Arthritis & Rheumatism 62, no. 7 (2010): 1974–1982.

[35] J. Du, J. J. Pfannkuche, G. Lang, et al., “Proinflammatory Intervertebral Disc Cell and Organ Culture Models Induced by Tumor Necrosis Factor Alpha,” JOR Spine 3, no. 3 (2020): e1104.

[36] A. L. A. Binch, A. A. Cole, L. M. Breakwell, et al., “Expression and Regulation of Neurotrophic and Angiogenic Factors During Human Intervertebral Disc Degeneration,” Arthritis Research & Therapy 16, no. 5 (2014): 416.

[37] K. R. Nakazawa, B. A. Walter, D. M. Laudier, et al., “Accumulation and Localization of Macrophage Phenotypes With Human Intervertebral Disc Degeneration,” Spine Journal 18, no. 2 (2018): 343–356.

[38] K. W. Kim, T. H. Lim, J. G. Kim, S. T. Jeong, K. Masuda, and H. S. An, “The Origin of Chondrocytes in the Nucleus Pulposus and Histologic Findings Associated With the Transition of a Notochordal Nucleus Pulposus to a Fibrocartilaginous Nucleus Pulposus in Intact Rabbit Intervertebral Discs,” Spine 28, no. 10 (2003): 982–990.

[39] A. J. Silva, J. R. Ferreira, C. Cunha, et al., “Macrophages Down-Regulate Gene Expression of Intervertebral Disc Degenerative Markers Under a Pro-Inflammatory Microenvironment,” Frontiers in Immunology 10 (2019): 1508.

[40] C. Yang, P. Cao, Y. Gao, et al., “Differential Expression of p38 Mapk Alpha, Beta, Gamma, Delta Isoforms in Nucleus Pulposus Modulates Macrophage Polarization in Intervertebral Disc Degeneration,” Scientific Reports 6 (2016): 22182.

[41] J. Wang, Y. Tian, K. L. E. Phillips, et al., “Tumor Necrosis Factor α– and Interleukin-1β–Dependent Induction of CCL3 Expression by Nucleus Pulposus Cells Promotes Macrophage Migration Through CCR1,” Arthritis & Rheumatism 65, no. 3 (2013): 832–842.

[42] T. Takada, K. Nishida, K. Maeno, et al., “Intervertebral Disc and Macrophage Interaction Induces Mechanical Hyperalgesia and Cytokine Production in a Herniated Disc Model in Rats,” Arthritis & Rheumatism 64, no. 8 (2012): 2601–2610.

[43] I. Prieto-Potin, R. Largo, J. A. Roman-Blas, G. Herrero-Beaumont, and D. A. Walsh, “Characterization of Multinucleated Giant Cells in Synovium and Subchondral Bone in Knee Osteoarthritis and Rheumatoid Arthritis,” BMC Musculoskeletal Disorders 16 (2015): 226.

[44] J. Sokolove and C. M. Lepus, “Role of Inflammation in the Pathogenesis of Osteoarthritis: Latest Findings and Interpretations,” Therapeutic Advances in Musculoskeletal Disease 5, no. 2 (2013): 77–94.

[45] M. V. Risbud and I. M. Shapiro, “Role of Cytokines in Intervertebral Disc Degeneration: Pain and Disc Content,” Nature Reviews Rheumatology 10, no. 1 (2014): 44–56.

[46] T. S. Griffith, T. Brunner, S. M. Fletcher, D. R. Green, and T. A. Ferguson, “Fas Ligand-Induced Apoptosis as a Mechanism of Immune Privilege,” Science 270, no. 5239 (1995): 1189–1192.

[47] A. Hiyama, J. Mochida, T. Iwashina, et al., “Transplantation of Mesenchymal Stem Cells in a Canine Disc Degeneration Model,” Journal of Orthopaedic Research 26, no. 5 (2008): 589–600.

[48] S. Kaneyama, K. Nishida, T. Takada, et al., “Fas Ligand Expression on Human Nucleus Pulposus Cells Decreases With Disc Degeneration Processes,” Journal of Orthopaedic Science 13, no. 2 (2008): 130–135.

[49] Y. Wang, M. Che, J. Xin, Z. Zheng, J. Li, and S. Zhang, “The Role of IL-1β and TNF-α in Intervertebral Disc Degeneration,” Biomedicine & Pharmacotherapy 131 (2020): 110660.

[50] P. Bermudez-Lekerika, K. B. Crump, S. Tseranidou, et al., “Immuno-Modulatory Effects of Intervertebral Disc Cells,” Frontiers in Cell and Developmental Biology 10 (2022): 924692.

[51] S. Kawaguchi, T. Yamashita, G. Katahira, H. Yokozawa, T. Torigoe, and N. Sato, “Chemokine Profile of Herniated Intervertebral Discs Infiltrated With Monocytes and Macrophages,” Spine 27, no. 14 (2002): 1511–1516.

[52] Y. H. Chung, M. H. Hu, S. C. Kao, et al., “Preclinical Animal Study and Pilot Clinical Trial of Using Enriched Peripheral Blood-Derived Mononuclear Cells for Intervertebral Disc Degeneration,” Cell Transplantation 33 (2024): 63689707.

[53] W. Li, Y. Zhao, Y. Wang, et al., “Deciphering the Sequential Changes of Monocytes/Macrophages in the Progression of IDD With Longitudinal Approach Using Single-Cell Transcriptome,” Frontiers in Immunology 14 (2023): 1090637.

[54] M. B. Goldring, “Chondrogenesis, Chondrocyte Differentiation, and Articular Cartilage Metabolism in Health and Osteoarthritis,” Therapeutic Advances in Musculoskeletal Disease 4, no. 4 (2012): 269–285.

[55] B. Peng, J. Hao, S. Hou, et al., “Possible Pathogenesis of Painful Intervertebral Disc Degeneration,” Spine 31, no. 5 (2006): 560–566.

[56] Z. Zhu, Z. He, T. Tang, et al., “Integrative Bioinformatics Analysis Revealed Mitochondrial Dysfunction-Related Genes Underlying Intervertebral Disc Degeneration,” Oxidative Medicine and Cellular Longevity 2022 (2022): 1372483.

[57] K. Murai, D. Sakai, Y. Nakamura, et al., “Primary Immune System Responders to Nucleus Pulposus Cells: Evidence for Immune Response in Disc Herniation,” European Cells and Materials 19 (2010): 13–21.

[58] S. W. Clayton, R. E. Walk, L. Mpofu, G. W. D. Easson, and S. Y. Tang, “Sex-Specific Divergences in the Types and Timing of Infiltrating Immune Cells During the Intervertebral Disc Acute Injury Response and Their Associations With Degeneration,” Osteoarthritis and Cartilage 33, no. 2 (2025): 247–260.

[59] A. Koskinen, K. Vuolteenaho, R. Nieminen, T. Moilanen, and E. Moilanen, “Leptin Enhances MMP-1, MMP-3 and MMP-13 Production in Human Osteoarthritic Cartilage and Correlates With MMP-1 and MMP-3 in Synovial Fluid From OA Patients,” Clinical and Experimental Rheumatology 29, no. 1 (2011): 57–64.

[60] C. López-Otín, M. A. Blasco, L. Partridge, M. Serrano, and G. Kroemer, “Hallmarks of Aging: An Expanding Universe,” Cell 186, no. 2 (2023): 243–278.

[61] Z. Cheng, W. Gan, Q. Xiang, et al., “Impaired Degradation of PLCG1 by Chaperone-Mediated Autophagy Promotes Cellular Senescence and Intervertebral Disc Degeneration,” Autophagy 21, no. 2 (2025): 352–373.

[62] H. E. Gruber, J. A. Ingram, H. J. Norton, and E. N. Hanley, “Senescence in Cells of the Aging and Degenerating Intervertebral Disc: Immunolocalization of Senescence-Associated β-Galactosidase in Human and Sand Rat Discs,” Spine 32, no. 3 (2007): 321–327.

[63] D. Purmessur, B. A. Walter, P. J. Roughley, D. M. Laudier, A. C. Hecht, and J. Iatridis, “A Role for TNFα in Intervertebral Disc Degeneration: A Non-Recoverable Catabolic Shift,” Biochemical and Biophysical Research Communications 433, no. 1 (2013): 151–156.

[64] J. He, A. Zhang, Z. Song, et al., “The Resistant Effect of SIRT1 in Oxidative Stress-Induced Senescence of Rat Nucleus Pulposus Cell Is Regulated by Akt-FoxO1 Pathway,” Bioscience Reports 39, no. 5 (2019): BSR20190112.

[65] C. Feng, Y. Zhang, M. Yang, et al., “Oxygen-Sensing Nox4 Generates Genotoxic ROS to Induce Premature Senescence of Nucleus Pulposus Cells Through MAPK and NF-KappaB Pathways,” Oxidative Medicine and Cellular Longevity 2017 (2017): 7426458.

[66] C. Feng, H. Liu, M. Yang, Y. Zhang, B. Huang, and Y. Zhou, “Disc Cell Senescence in Intervertebral Disc Degeneration: Causes and Molecular Pathways,” Cell Cycle 15, no. 13 (2016): 1674–1684.

[67] H. Che, J. Li, Y. Li, et al., “p16 Deficiency Attenuates Intervertebral Disc Degeneration by Adjusting Oxidative Stress and Nucleus Pulposus Cell Cycle,” eLife 9 (2020): e52570.

[68] S. Liu, S. Yao, H. Yang, S. Liu, and Y. Wang, “Autophagy: Regulator of Cell Death,” Cell Death & Disease 14, no. 10 (2023): 648.

[69] K. G. Ma, Z. W. Shao, S. H. Yang, et al., “Autophagy Is Activated in Compression-Induced Cell Degeneration and Is Mediated by Reactive Oxygen Species in Nucleus Pulposus Cells Exposed to Compression,” Osteoarthritis and Cartilage 21, no. 12 (2013): 2030–2038.

[70] L. Jiang, Y. Jin, H. Wang, Y. Jiang, and J. Dong, “Glucosamine Protects Nucleus Pulposus Cells and Induces Autophagy via the mTOR-Dependent Pathway,” Journal of Orthopaedic Research 32, no. 11 (2014): 1532–1542.

[71] J. W. Chen, B. B. Ni, B. Li, Y. H. Yang, S. D. Jiang, and L. S. Jiang, “The Responses of Autophagy and Apoptosis to Oxidative Stress in Nucleus Pulposus Cells: Implications for Disc Degeneration,” Cellular Physiology and Biochemistry 34, no. 4 (2014): 1175–1189.

[72] R. He, Z. Wang, M. Cui, et al., “HIF1A Alleviates Compression-Induced Apoptosis of Nucleus Pulposus Derived Stem Cells via Upregulating Autophagy,” Autophagy 17, no. 11 (2021): 3338–3360.

[73] C. Shen, J. Yan, L. S. Jiang, and L. Y. Dai, “Autophagy in Rat Annulus Fibrosus Cells: Evidence and Possible Implications,” Arthritis Research & Therapy 13, no. 4 (2011): R132.

[74] K. Hashimoto, R. O. C. Oreffo, M. B. Gibson, M. B. Goldring, and H. I. Roach, “Dna Demethylation at Specific CpG Sites in the IL1B Promoter in Response to Inflammatory Cytokines in Human Articular Chondrocytes,” Arthritis & Rheumatism 60, no. 11 (2009): 3303–3313.

[75] S. Miyaki, T. Sato, A. Inoue, et al., “MicroRNA-140 Plays Dual Roles in Both Cartilage Development and Homeostasis,” Genes & Development 24, no. 11 (2010): 1173–1185.

[76] T. Rich, C. J. Watson, and A. Wyllie, “Apoptosis: The Germs of Death,” Nature Cell Biology 1, no. 3 (1999): E69–E71.

[77] Y. Han, X. Li, M. Yan, et al., “Oxidative Damage Induces Apoptosis and Promotes Calcification in Disc Cartilage Endplate Cell Through ROS/MAPK/NF-κB Pathway: Implications for Disc Degeneration,” Biochemical and Biophysical Research Communications 516, no. 3 (2019): 1026–1032.

[78] D. Yao, M. Li, K. Wang, et al., “Emodin Ameliorates Matrix Degradation and Apoptosis in Nucleus Pulposus Cells and Attenuates Intervertebral Disc Degeneration Through LRP1 In Vitro and In Vivo,” Experimental Cell Research 432, no. 2 (2023): 113794.

[79] H. Chen, J. Wang, B. Hu, et al., “MiR-34a Promotes Fas-Mediated Cartilage Endplate Chondrocyte Apoptosis by Targeting BCL-2,” Molecular and Cellular Biochemistry 406, no. 1–2 (2015): 21–30.

[80] H. W. Chen, M. Q. Liu, G. Z. Zhang, et al., “Proanthocyanidins Inhibit the Apoptosis and Aging of Nucleus Pulposus Cells Through the PI3K/Akt Pathway Delaying Intervertebral Disc Degeneration,” Connective Tissue Research 63, no. 6 (2022): 650–662.

[81] D. Wang, X. He, D. Wang, et al., “Quercetin Suppresses Apoptosis and Attenuates Intervertebral Disc Degeneration via the SIRT1-Autophagy Pathway,” Frontiers in Cell and Developmental Biology 8 (2020): 613006.

[82] K. Wang, D. Yao, Y. Li, et al., “TAK-715 Alleviated IL-1β-Induced Apoptosis and ECM Degradation in Nucleus Pulposus Cells and Attenuated Intervertebral Disc Degeneration Ex Vivo and In Vivo,” Arthritis Research & Therapy 25, no. 1 (2023): 45.

[83] R. Liu-Bryan and R. Terkeltaub, “Chondrocyte Innate Immune Myeloid Differentiation Factor 88-Dependent Signaling Drives Procatabolic Effects of the Endogenous Toll-Like Receptor 2/Toll-Like Receptor 4 Ligands Low Molecular Weight Hyaluronan and High Mobility Group Box Chromosomal Protein 1 in Mice,” Arthritis and Rheumatism 62, no. 7 (2010): 2004–2012.

[84] K. E. Happonen, T. Saxne, A. Aspberg, M. Mörgelin, D. Heinegård, and A. M. Blom, “Regulation of Complement by Cartilage Oligomeric Matrix Protein Allows for a Novel Molecular Diagnostic Principle in Rheumatoid Arthritis,” Arthritis & Rheumatism 62, no. 12 (2010): 3574–3583.

[85] J. Shi, W. Gao, and F. Shao, “Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death,” Trends in Biochemical Sciences 42, no. 4 (2017): 245–254.

[86] Z. Bai, W. Liu, D. He, et al., “Protective Effects of Autophagy and NFE2L2 on Reactive Oxygen Species-Induced Pyroptosis of Human Nucleus Pulposus Cells,” Aging 12, no. 8 (2020): 7534–7548.

[87] Y. Zhao, C. Qiu, W. Wang, et al., “Cortistatin Protects Against Intervertebral Disc Degeneration Through Targeting Mitochondrial ROS-Dependent NLRP3 Inflammasome Activation,” Theranostics 10, no. 15 (2020): 7015–7033.

[88] K. Zhao, R. An, Q. Xiang, et al., “Acid-Sensing Ion Channels Regulate Nucleus Pulposus Cell Inflammation and Pyroptosis via the NLRP3 Inflammasome in Intervertebral Disc Degeneration,” Cell Proliferation 54, no. 1 (2021): e12941.

[89] J. Xu, Y. Jiang, J. Wang, et al., “Macrophage Endocytosis of High-Mobility Group Box 1 Triggers Pyroptosis,” Cell Death & Differentiation 21, no. 8 (2014): 1229–1239.

[90] R. Zhou, A. Tardivel, B. Thorens, I. Choi, and J. Tschopp, “Thioredoxin-Interacting Protein Links Oxidative Stress to Inflammasome Activation,” Nature Immunology 11, no. 2 (2010): 136–140.

[91] Y. Zhou, Z. Chen, X. Yang, et al., “Morin Attenuates Pyroptosis of Nucleus Pulposus Cells and Ameliorates Intervertebral Disc Degeneration via Inhibition of the TXNIP/NLRP3/Caspase-1/IL-1β Signaling Pathway,” Biochemical and Biophysical Research Communications 559 (2021): 106–112.

[92] Y. Wang, Y. Li, J. Wang, et al., “Maresin 1 Attenuates Radicular Pain Through the Inhibition of NLRP3 Inflammasome-Induced Pyroptosis via NF-κB Signaling,” Frontiers in Neuroscience 14 (2020): 831.

[93] H. Ma, C. Xie, Z. Chen, et al., “MFG-E8 Alleviates Intervertebral Disc Degeneration by Suppressing Pyroptosis and Extracellular Matrix Degradation in Nucleus Pulposus Cells via Nrf2/TXNIP/NLRP3 Axis,” Cell Death Discovery 8, no. 1 (2022): 209.

[94] J. Wang, Y. Jiang, C. Zhu, et al., “Mitochondria-Engine With Self-Regulation to Restore Degenerated Intervertebral Disc Cells via Bioenergetic Robust Hydrogel Design,” Bioactive Materials 43 (2024): 340–341.

[95] Z. Ma, P. Tang, W. Dong, et al., “SIRT1 Alleviates IL-1beta Induced Nucleus Pulposus Cells Pyroptosis via Mitophagy in Intervertebral Disc Degeneration,” International Immunopharmacology 107 (2022): 108671.

[96] X. Jiang, B. R. Stockwell, and M. Conrad, “Ferroptosis: Mechanisms, Biology and Role in Disease,” Nature Reviews Molecular Cell Biology 22, no. 4 (2021): 266–282.

[97] J. Z. Li, B. Y. Fan, T. Sun, et al., “Bioinformatics Analysis of Ferroptosis in Spinal Cord Injury,” Neural Regeneration Research 18, no. 3 (2023): 626–633.

[98] Y. Li, D. Pan, X. Wang, et al., “Silencing ATF3 Might Delay TBHP-Induced Intervertebral Disc Degeneration by Repressing NPC Ferroptosis, Apoptosis, and ECM Degradation,” Oxidative Medicine and Cellular Longevity 2022 (2022): 4235126.

[99] Y. Zhang, S. Han, M. Kong, Q. Tu, L. Zhang, and X. Ma, “Single-Cell RNA-Seq Analysis Identifies Unique Chondrocyte Subsets and Reveals Involvement of Ferroptosis in Human Intervertebral Disc Degeneration,” Osteoarthritis and Cartilage 29, no. 9 (2021): 1324–1334.

[100] S. Li, Z. Liao, H. Yin, et al., “G3BP1 Coordinates Lysophagy Activity to Protect Against Compression-Induced Cell Ferroptosis During Intervertebral Disc Degeneration,” Cell Proliferation 56, no. 3 (2023): e13368.

[101] X. Yu, H. Xu, Q. Liu, et al., “circ_0072464 Shuttled by Bone Mesenchymal Stem Cell-Secreted Extracellular Vesicles Inhibits Nucleus Pulposus Cell Ferroptosis to Relieve Intervertebral Disc Degeneration,” Oxidative Medicine and Cellular Longevity 2022 (2022): 2948090.

[102] F. Wang, J. Li, Y. Zhao, et al., “miR-672-3p Promotes Functional Recovery in Rats With Contusive Spinal Cord Injury by Inhibiting Ferroptosis Suppressor Protein 1,” Oxidative Medicine and Cellular Longevity 2022 (2022): 6041612.

[103] C. Shao, Y. Chen, T. Yang, H. Zhao, and D. Li, “Mesenchymal Stem Cell Derived Exosomes Suppress Neuronal Cell Ferroptosis via lncGm36569/miR-5627-5p/FSP1 Axis in Acute Spinal Cord Injury,” Stem Cell Reviews and Reports 18, no. 3 (2022): 1127–1142.

[104] X. Zhang, Z. Huang, Z. Xie, et al., “Homocysteine Induces Oxidative Stress and Ferroptosis of Nucleus Pulposus via Enhancing Methylation of GPX4,” Free Radical Biology and Medicine 160 (2020): 552–565.

[105] P. Zhang, K. Rong, J. Guo, et al., “Cynarin Alleviates Intervertebral Disc Degeneration via Protecting Nucleus Pulposus Cells From Ferroptosis,” Biomedicine & Pharmacotherapy 165 (2023): 115252.

[106] D. B. Burr, “Anatomy and Physiology of the Mineralized Tissues: Role in the Pathogenesis of Osteoarthrosis,” Osteoarthritis and Cartilage 12 Suppl A (2004): S20–S30.

[107] X. Cai, Y. Liu, Y. Hu, et al., “ROS-Mediated Lysosomal Membrane Permeabilization Is Involved in Bupivacaine-Induced Death of Rabbit Intervertebral Disc Cells,” Redox Biology 18 (2018): 65–76.

[108] G. Kroemer and M. Jäättelä, “Lysosomes and Autophagy in Cell Death Control,” Nature Reviews Cancer 5, no. 11 (2005): 886–897.

[109] A. D. Theocharis, S. S. Skandalis, C. Gialeli, and N. K. Karamanos, “Extracellular Matrix Structure,” Advanced Drug Delivery Reviews 97 (2016): 4–27.

[110] P. J. Roughley, L. I. Melching, T. F. Heathfield, R. H. Pearce, and J. S. Mort, “The Structure and Degradation of Aggrecan in Human Intervertebral Disc,” European Spine Journal 15 (2006): 326–332.

[111] L. Kang, Q. Xiang, S. Zhan, et al., “Restoration of Autophagic Flux Rescues Oxidative Damage and Mitochondrial Dysfunction to Protect Against Intervertebral Disc Degeneration,” Oxidative Medicine and Cellular Longevity 2019 (2019): 7810320.

[112] D. Sakai, Y. Nakamura, T. Nakai, et al., “Exhaustion of Nucleus Pulposus Progenitor Cells With Ageing and Degeneration of the Intervertebral Disc,” Nature Communications 3 (2012): 1264.

[113] B. V. Fearing, L. Jing, M. N. Barcellona, et al., “Mechanosensitive Transcriptional Coactivators MRTF-A and YAP/TAZ Regulate Nucleus Pulposus Cell Phenotype Through Cell Shape,” FASEB Journal 33, no. 12 (2019): 14022–14035.

[114] J. Speer, M. Barcellona, L. Jing, et al., “Integrin-Mediated Interactions With a Laminin-Presenting Substrate Modulate Biosynthesis and Phenotypic Expression for Cells of the Human Nucleus Pulposus,” European Cells and Materials 41 (2021): 793–810.

[115] M. J. Benito, D. J. Veale, O. Fitzgerald, W. B. van den Berg, and B. Bresnihan, “Synovial Tissue Inflammation in Early and Late Osteoarthritis,” Annals of the Rheumatic Diseases 64, no. 9 (2005): 1263–1267.

[116] J. Sellam and F. Berenbaum, “The Role of Synovitis in Pathophysiology and Clinical Symptoms of Osteoarthritis,” Nature Reviews Rheumatology 6, no. 11 (2010): 625–635.

[117] J. Conde, R. Gomez, G. Bianco, et al., “Expanding the Adipokine Network in Cartilage: Identification and Regulation of Novel Factors in Human and Murine Chondrocytes,” Annals of the Rheumatic Diseases 70, no. 3 (2011): 551–559.

[118] A. Koskinen, K. Vuolteenaho, R. Nieminen, T. Moilanen, and E. Moilanen, “Leptin Enhances MMP-1, MMP-3 and MMP-13 Production in Human Osteoarthritic Cartilage and Correlates With MMP-1 and MMP-3 in Synovial Fluid From Oa Patients,” Clinical and Experimental Rheumatology 29, no. 1 (2011): 57–64.

[119] R. R. Manoharan, A. Prasad, P. Pospíšil, and J. Kzhyshkowska, “ROS Signaling in Innate Immunity via Oxidative Protein Modifications,” Frontiers in Immunology 15 (2024): 1359600.

[120] B. Halliwell, A. Adhikary, M. Dingfelder, and M. Dizdaroglu, “Hydroxyl Radical Is a Significant Player in Oxidative DNA Damage In Vivo,” Chemical Society Reviews 50, no. 15 (2021): 8355–8360.

[121] B. Kalyanaraman, “Teaching the Basics of Redox Biology to Medical and Graduate Students: Oxidants, Antioxidants and Disease Mechanisms,” Redox Biology 1, no. 1 (2013): 244–257.

[122] T. F. Brewer, F. J. Garcia, C. S. Onak, K. S. Carroll, and C. J. Chang, “Chemical Approaches to Discovery and Study of Sources and Targets of Hydrogen Peroxide Redox Signaling Through NADPH Oxidase Proteins,” Annual Review of Biochemistry 84 (2015): 765–790.

[123] Y. Wang, H. Cheng, T. Wang, K. Zhang, Y. Zhang, and X. Kang, “Oxidative Stress in Intervertebral Disc Degeneration: Molecular Mechanisms, Pathogenesis and Treatment,” Cell Proliferation 56, no. 9 (2023): e13448.

[124] Y. Li, L. Chen, Y. Gao, X. Zou, and F. Wei, “Oxidative Stress and Intervertebral Disc Degeneration: Pathophysiology, Signaling Pathway, and Therapy,” Oxidative Medicine and Cellular Longevity 2022 (2022): 1984742.

[125] D. B. Zorov, M. Juhaszova, and S. J. Sollott, “Mitochondrial Reactive Oxygen Species (ROS) and Ros-Induced Ros Release,” Physiological Reviews 94, no. 3 (2014): 909–950.

[126] J. Kim, M. Xu, R. Xo, et al., “Mitochondrial DNA Damage Is Involved in Apoptosis Caused by Pro-Inflammatory Cytokines in Human OA Chondrocytes,” Osteoarthritis and Cartilage 18, no. 3 (2010): 424–432.

[127] H. Yu, G. Hou, J. Cao, Y. Yin, Y. Zhao, and L. Cheng, “Mangiferin Alleviates Mitochondrial ROS in Nucleus Pulposus Cells and Protects Against Intervertebral Disc Degeneration via Suppression of NF-KappaB Signaling Pathway,” Oxidative Medicine and Cellular Longevity 2021 (2021): 6632786.

[128] Z. Tang, B. Hu, F. Zang, J. Wang, X. Zhang, and H. Chen, “Nrf2 Drives Oxidative Stress-Induced Autophagy in Nucleus Pulposus Cells via a Keap1/Nrf2/p62 Feedback Loop to Protect Intervertebral Disc From Degeneration,” Cell Death & Disease 10, no. 7 (2019): 510.

[129] Y. Lu, L. Zhou, S. He, H. L. Ren, N. Zhou, and Z. M. Hu, “Lycopene Alleviates Disc Degeneration Under Oxidative Stress Through the Nrf2 Signaling Pathway,” Molecular and Cellular Probes 51 (2020): 101559.

[130] L. Kang, S. Liu, J. Li, Y. Tian, Y. Xue, and X. Liu, “Parkin and Nrf2 Prevent Oxidative Stress-Induced Apoptosis in Intervertebral Endplate Chondrocytes via Inducing Mitophagy and Anti-Oxidant Defenses,” Life Sciences 243 (2020): 117244.

[131] A. Oeckinghaus, M. S. Hayden, and S. Ghosh, “Crosstalk in NF-κB Signaling Pathways,” Nature Immunology 12, no. 8 (2011): 695–708.

[132] Y. Takada, A. Mukhopadhyay, G. C. Kundu, G. H. Mahabeleshwar, S. Singh, and B. B. Aggarwal, “Hydrogen Peroxide Activates NF-κB Through Tyrosine Phosphorylation of IκBα and Serine Phosphorylation of P65,” Journal of Biological Chemistry 278, no. 26 (2003): 24233–24241.

[133] N. L. Reynaert, A. van der Vliet, A. S. Guala, et al., “Dynamic Redox Control of NF-κB Through Glutaredoxin-Regulated S-Glutathionylation of Inhibitory κB Kinase Β,” Proceedings of the National Academy of Sciences 103, no. 35 (2006): 13086–13091.

[134] A. G. Nerlich, B. E. Bachmeier, E. Schleicher, H. Rohrbach, G. Paesold, and N. Boos, “Immunomorphological Analysis of RAGE Receptor Expression and NF-κB Activation in Tissue Samples From Normal and Degenerated Intervertebral Discs of Various Ages,” Annals of the New York Academy of Sciences 1096 (2007): 239–248.

[135] J. Li, J. Li, C. Cao, et al., “Melatonin Inhibits Annulus Fibrosus Cell Senescence Through Regulating the ROS/NF-Kappab Pathway in an Inflammatory Environment,” BioMed Research International 2021 (2021): 3456321.

[136] J. Y. Fang and B. C. Richardson, “The MAPK Signalling Pathways and Colorectal Cancer,” Lancet Oncology 6, no. 5 (2005): 322–327.

[137] A. Dimozi, E. Mavrogonatou, A. Sklirou, and D. Kletsas, “Oxidative Stress Inhibits the Proliferation, Induces Premature Senescence and Promotes a Catabolic Phenotype in Human Nucleus Pulposus Intervertebral Disc Cells,” European Cells and Materials 30 (2015): 89–103.

[138] S. Suzuki, N. Fujita, N. Hosogane, et al., “Excessive Reactive Oxygen Species Are Therapeutic Targets for Intervertebral Disc Degeneration,” Arthritis Research & Therapy 17 (2015): 316.

[139] J. Wang, K. Hu, X. Cai, et al., “Targeting PI3K/AKT Signaling for Treatment of Idiopathic Pulmonary Fibrosis,” Acta Pharmaceutica Sinica B 12, no. 1 (2022): 18–32.

[140] F. Xu, L. Na, Y. Li, and L. Chen, “Retracted Article: Roles of the PI3K/AKT/mTOR Signalling Pathways in Neurodegenerative Diseases and Tumours,” Cell & Bioscience 10, no. 1 (2020): 54.

[141] Y. Lin, W. Guo, K. W. Chen, and Z. M. Xiao, “VO-OHpic Attenuates Intervertebral Disc Degeneration via PTEN/Akt Pathway,” European Review for Medical and Pharmacological Sciences 24, no. 6 (2020): 2811–2819.

[142] O. Krupkova, J. Handa, M. Hlavna, et al., “The Natural Polyphenol Epigallocatechin Gallate Protects Intervertebral Disc Cells From Oxidative Stress,” Oxidative Medicine and Cellular Longevity 2016 (2016): 7031397.

[143] L. P. Nan, F. Wang, D. Ran, et al., “Naringin Alleviates H(2)O(2)-Induced Apoptosis via the PI3K/Akt Pathway in Rat Nucleus Pulposus-Derived Mesenchymal Stem Cells,” Connective Tissue Research 61, no. 6 (2020): 554–567.

[144] P. Wang, S. Zhang, W. Liu, et al., “Bardoxolone Methyl Breaks the Vicious Cycle Between M1 Macrophages and Senescent Nucleus Pulposus Cells Through the Nrf2/STING/NF-kappaB Pathway,” International Immunopharmacology 127 (2024): 111262.

[145] Y. Tian, Z. Bao, Y. Ji, X. Mei, and H. Yang, “Epigallocatechin-3-Gallate Protects H(2)O(2)-Induced Nucleus Pulposus Cell Apoptosis and Inflammation by Inhibiting cGAS/Sting/NLRP3 Activation,” Drug Design, Development and Therapy 14 (2020): 2113–2122.

[146] Z. Chen, C. Chen, X. Yang, et al., “Dysfunction of STING Autophagy Degradation in Senescent Nucleus Pulposus Cells Accelerates Intervertebral Disc Degeneration,” International Journal of Biological Sciences 20, no. 7 (2024): 2370–2387.

[147] J. Zappia, Q. Tong, R. Van der Cruyssen, et al., “Osteomodulin Downregulation Is Associated With Osteoarthritis Development,” Bone Research 11, no. 1 (2023): 49.

[148] L. Gao, J. Zhuang, L. Nie, et al., “Intrinsic Peroxidase-Like Activity of Ferromagnetic Nanoparticles,” Nature Nanotechnology 2, no. 9 (2007): 577–583.

[149] B. Garg and T. Bisht, “Carbon Nanodots as Peroxidase Nanozymes for Biosensing,” Molecules 21, no. 12 (2016): 1653.

[150] T. Li, Y. Wang, W. Liu, H. Fei, C. Guo, and H. Wei, “Nanoconfinement-Guided Construction of Nanozymes for Determining H(2) O(2) Produced by Sonication,” Angewandte Chemie International Edition 62, no. 12 (2023): e202212438.

[151] S. Huang, J. Li, Y. Lin, et al., “Hydrogen-Bonded Supramolecular Nanotrap Enabling the Interfacial Activation of Hosted Enzymes,” Journal of the American Chemical Society 146, no. 3 (2024): 1967–1976.

[152] S. B. Bankar, M. V. Bule, R. S. Singhal, and L. Ananthanarayan, “Glucose Oxidase--An Overview,” Biotechnology Advances 27, no. 4 (2009): 489–501.

[153] H. Chai, Y. Li, K. Yu, et al., “Two-Site Enhanced Porphyrinic Metal-Organic Framework Nanozymes and Nano-/Bioenzyme Confined Catalysis for Colorimetric/Chemiluminescent Dual-Mode Visual Biosensing,” Analytical Chemistry 95, no. 44 (2023): 16383–16391.

[154] M. Li, J. Chen, W. Wu, Y. Fang, and S. Dong, “Oxidase-Like MOF-818 Nanozyme With High Specificity for Catalysis of Catechol Oxidation,” Journal of the American Chemical Society 142, no. 36 (2020): 15569–15574.

[155] D. Harman, “Free Radical Theory of Aging,” Mutation Research/DNAging 275, no. 3–6 (1992): 257–266.

[156] J. D. Crapo, T. Oury, C. Rabouille, J. W. Slot, and L. Y. Chang, “Copper, Zinc Superoxide Dismutase Is Primarily a Cytosolic Protein in Human Cells,” Proceedings of the National Academy of Sciences 89, no. 21 (1992): 10405–10409.

[157] L. Li, H. Li, L. Shi, L. Shi, and T. Li, “Tin Porphyrin-Based Nanozymes With Unprecedented Superoxide Dismutase-Mimicking Activities,” Langmuir 38, no. 23 (2022): 7272–7279.

[158] I. von Ossowski, G. Hausner, and P. C. Loewen, “Molecular Evolutionary Analysis Based on the Amino Acid Sequence of Catalase,” Journal of Molecular Evolution 37, no. 1 (1993): 71–76.

[159] L. Meng, Y. Cheng, S. Gan, et al., “Facile Deposition of Manganese Dioxide to Albumin-Bound Paclitaxel Nanoparticles for Modulation of Hypoxic Tumor Microenvironment to Improve Chemoradiation Therapy,” Molecular Pharmaceutics 15, no. 2 (2018): 447–457.

[160] C. Wang, Y. Li, W. Yang, L. Zhou, and S. Wei, “Nanozyme With Robust Catalase Activity by Multiple Mechanisms and Its Application for Hypoxic Tumor Treatment,” Advanced Healthcare Materials 10, no. 19 (2021): e2100601.

[161] J. Pei, X. Pan, G. Wei, and Y. Hua, “Research Progress of Glutathione Peroxidase Family (GPX) in Redoxidation,” Frontiers in Pharmacology 14 (2023): 1147414.

[162] A. A. Vernekar, D. Sinha, S. Srivastava, P. U. Paramasivam, P. D'Silva, and G. Mugesh, “An Antioxidant Nanozyme That Uncovers the Cytoprotective Potential of Vanadia Nanowires,” Nature Communications 5 (2014): 5301.

[163] L. Wang, Z. Hu, S. Wu, J. Pan, X. Xu, and X. Niu, “A Peroxidase-Mimicking Zr-Based MOF Colorimetric Sensing Array to Quantify and Discriminate Phosphorylated Proteins,” Analytica Chimica Acta 1121 (2020): 26–34.

[164] R. Zhang, K. Fan, and X. Yan, “Nanozymes: Created by Learning From Nature,” Science China Life Sciences 63, no. 8 (2020): 1183–1200.

[165] J. Chen, Q. Ma, M. Li, et al., “Glucose-Oxidase Like Catalytic Mechanism of Noble Metal Nanozymes,” Nature Communications 12, no. 1 (2021): 3375.

[166] Q. Liu, A. Zhang, R. Wang, Q. Zhang, and D. Cui, “A Review on Metal- and Metal Oxide-Based Nanozymes: Properties, Mechanisms, and Applications,” Nano-Micro Letters 13, no. 1 (2021): 154.

[167] Y. Song, X. Wang, C. Zhao, K. Qu, J. Ren, and X. Qu, “Label-Free Colorimetric Detection of Single Nucleotide Polymorphism by Using Single-Walled Carbon Nanotube Intrinsic Peroxidase-Like Activity,” Chemistry – A European Journal 16, no. 12 (2010): 3617–3621.

[168] H. Wei and E. Wang, “Nanomaterials With Enzyme-Like Characteristics (Nanozymes): Next-Generation Artificial Enzymes,” Chemical Society Reviews 42, no. 14 (2013): 6060–6093.

[169] T. M. Allen and P. R. Cullis, “Liposomal Drug Delivery Systems: From Concept to Clinical Applications,” Advanced Drug Delivery Reviews 65, no. 1 (2013): 36–48.

[170] K. M. El-Say and H. S. El-Sawy, “Polymeric Nanoparticles: Promising Platform for Drug Delivery,” International Journal of Pharmaceutics 528, no. 1–2 (2017): 675–691.

[171] M. J. Mitchell, M. M. Billingsley, R. M. Haley, M. E. Wechsler, N. A. Peppas, and R. Langer, “Engineering Precision Nanoparticles for Drug Delivery,” Nature Reviews Drug Discovery 20, no. 2 (2021): 101–124.

[172] H. Cabral, K. Miyata, K. Osada, and K. Kataoka, “Block Copolymer Micelles in Nanomedicine Applications,” Chemical Reviews 118, no. 14 (2018): 6844–6892.

[173] Y. Liang, L. Duan, J. Lu, and J. Xia, “Engineering Exosomes for Targeted Drug Delivery,” Theranostics 11, no. 7 (2021): 3183–3195.

[174] A. M. Elsherbini and S. A. Sabra, “Nanoparticles-in-Nanofibers Composites: Emphasis on Some Recent Biomedical Applications,” Journal of Controlled Release 348 (2022): 57–83.

[175] K. Ganguly, K. Chaturvedi, U. A. More, M. N. Nadagouda, and T. M. Aminabhavi, “Polysaccharide-Based Micro/Nanohydrogels for Delivering Macromolecular Therapeutics,” Journal of Controlled Release 193 (2014): 162–173.

[176] R. Dutta and R. I. Mahato, “Recent Advances in Hepatocellular Carcinoma Therapy,” Pharmacology & Therapeutics 173 (2017): 106–117.

[177] B. Yu, X. Zhao, L. J. Lee, and R. J. Lee, “Targeted Delivery Systems for Oligonucleotide Therapeutics,” AAPS Journal 11, no. 1 (2009): 195–203.

[178] H. B. Newton, “Advances in Strategies to Improve Drug Delivery to Brain Tumors,” Expert Review of Neurotherapeutics 6, no. 10 (2006): 1495–1509.

[179] J. O. Eloy, R. Petrilli, L. N. F. Trevizan, and M. Chorilli, “Immunoliposomes: A Review on Functionalization Strategies and Targets for Drug Delivery,” Colloids and Surfaces B: Biointerfaces 159 (2017): 454–467.

[180] M. Sarfraz, A. Afzal, T. Yang, et al., “Development of Dual Drug Loaded Nanosized Liposomal Formulation by A Reengineered Ethanolic Injection Method and Its Pre-Clinical Pharmacokinetic Studies,” Pharmaceutics 10, no. 3 (2018): 151.

[181] Y. J. Kang, E. G. Cutler, and H. Cho, “Therapeutic Nanoplatforms and Delivery Strategies for Neurological Disorders,” Nano Convergence 5, no. 1 (2018): 35.

[182] S. Y. Chong, X. Wang, L. van Bloois, et al., “Injectable Liposomal Docosahexaenoic Acid Alleviates Atherosclerosis Progression and Enhances Plaque Stability,” Journal of Controlled Release 360 (2023): 344–364.

[183] Z. Li, H. Zhu, H. Liu, et al., “Synergistic Dual Cell Therapy for Atherosclerosis Regression: Ros-Responsive Bio-Liposomes Co-Loaded With Geniposide and Emodin,” Journal of Nanobiotechnology 22, no. 1 (2024): 129.

[184] M. Sela, M. Poley, P. Mora-Raimundo, et al., “Brain-Targeted Liposomes Loaded With Monoclonal Antibodies Reduce Alpha-Synuclein Aggregation and Improve Behavioral Symptoms in Parkinson's Disease,” Advanced Materials 35, no. 51 (2023): e2304654.

[185] S. Jiang, G. Cai, Z. Yang, et al., “Biomimetic Nanovesicles as a Dual Gene Delivery System for the Synergistic Gene Therapy of Alzheimer's Disease,” ACS Nano 18, no. 18 (2024): 11753–11768.

[186] S. Wang, Y. Zhang, Y. Zhong, et al., “Accelerating Diabetic Wound Healing by ROS-Scavenging Lipid Nanoparticle-mRNA Formulation,” Proceedings of the National Academy of Sciences 121, no. 22 (2024): e1972032175.

[187] N. Yatim, S. Cullen, and M. L. Albert, “Dying Cells Actively Regulate Adaptive Immune Responses,” Nature Reviews Immunology 17, no. 4 (2017): 262–275.

[188] X. Chen, F. Meng, Y. Xu, T. Li, X. Chen, and H. Wang, “Chemically Programmed STING-Activating Nano-Liposomal Vesicles Improve Anticancer Immunity,” Nature Communications 14, no. 1 (2023): 4584.

[189] P. Kothamasu, H. Kanumur, N. Ravur, C. Maddu, R. Parasuramrajam, and S. Thangavel, “Nanocapsules: The Weapons for Novel Drug Delivery Systems,” BioImpacts: BI 2, no. 2 (2012): 71–81.

[190] V. S. Madamsetty, S. Tavakol, S. Moghassemi, et al., “Chitosan: A Versatile Bio-Platform for Breast Cancer Theranostics,” Journal of Controlled Release 341 (2022): 733–752.

[191] D. Modi, I. Mohammad, M. H. Warsi, et al., “Formulation Development, Optimization, and In Vitro Assessment of Thermoresponsive Ophthalmic Pluronic F127-chitosan In Situ Tacrolimus Gel,” Journal of Biomaterials Science, Polymer Edition 32, no. 13 (2021): 1678–1702.

[192] F. Colella, J. P. Garcia, M. Sorbona, et al., “Drug Delivery in Intervertebral Disc Degeneration and Osteoarthritis: Selecting the Optimal Platform for the Delivery of Disease-Modifying Agents,” Journal of Controlled Release 328 (2020): 985–999.

[193] M. Yokoyama, G. S. Kwon, T. Okano, Y. Sakurai, T. Seto, and K. Kataoka, “Preparation of Micelle-Forming Polymer-Drug Conjugates,” Bioconjugate Chemistry 3, no. 4 (1992): 295–301.

[194] J. J. Hu, N. Lin, Y. Zhang, F. Xia, and X. Lou, “Nanofibers in Organelles: From Structure Design to Biomedical Applications,” Angewandte Chemie International Edition 63, no. 5 (2024): e202313139.

[195] C. Dalwadi and G. Patel, “Application of Nanohydrogels in Drug Delivery Systems: Recent Patents Review,” Recent Patents on Nanotechnology 9, no. 1 (2015): 17–25.

[196] C. Wang, Z. Li, Y. Liu, and L. Yuan, “Exosomes in Atherosclerosis: Performers, Bystanders, Biomarkers, and Therapeutic Targets,” Theranostics 11, no. 8 (2021): 3996–4010.

[197] H. Wang, Y. Ding, W. Zhang, et al., “Oxymatrine Liposomes for Intervertebral Disc Treatment: Formulation, In Vitro and In Vivo Assessments,” Drug Design, Development and Therapy 14 (2020): 921–931.

[198] L. Xiao, R. Huang, Y. Zhang, et al., “A New Formyl Peptide Receptor-1 Antagonist Conjugated Fullerene Nanoparticle for Targeted Treatment of Degenerative Disc Diseases,” ACS Applied Materials & Interfaces 11, no. 42 (2019): 38405–38416.

[199] L. Jin, M. Ding, A. Oklopcic, et al., “Nanoparticle Fullerol Alleviates Radiculopathy via NLRP3 Inflammasome and Neuropeptides,” Nanomedicine: Nanotechnology, Biology and Medicine 13, no. 6 (2017): 2049–2059.

[200] C. H. Yeh, D. Chen, B. Aghdasi, et al., “Link Protein N-Terminal Peptide and Fullerol Promote Matrix Production and Decrease Degradation Enzymes in Rabbit Annulus Cells,” Connective Tissue Research 59, no. 2 (2018): 191–200.

[201] B. Ding, P. Zheng, P. Ma, and J. Lin, “Manganese Oxide Nanomaterials: Synthesis, Properties, and Theranostic Applications,” Advanced Materials 32, no. 10 (2020): e1905823.

[202] W. Zhang, M. Yang, T. Sun, et al., “Can Manganese Dioxide Microspheres Be Used as Intermediaries to Alleviate Intervertebral Disc Degeneration With Strengthening Drugs?,” Frontiers in Bioengineering and Biotechnology 10 (2022): 866290.

[203] C. Liu, L. Xiao, Y. Zhang, Q. Zhao, and H. Xu, “Regeneration of Annulus Fibrosus Tissue Using a DAFM/PECUU-Blended Electrospun Scaffold,” Journal of Biomaterials Science, Polymer Edition 31, no. 18 (2020): 2347–2361.

[204] Z. Sun, H. Zhao, B. Liu, et al., “AF Cell Derived Exosomes Regulate Endothelial Cell Migration and Inflammation: Implications for Vascularization in Intervertebral Disc Degeneration,” Life Sciences 265 (2021): 118778.

[205] K. Li, W. Yang, X. Chen, et al., “A Structured Biomimetic Nanoparticle as Inflammatory Factor Sponge and Autophagy-Regulatory Agent Against Intervertebral Disc Degeneration and Discogenic Pain,” Journal of Nanobiotechnology 22, no. 1 (2024): 486.

[206] C. H. Chen, S. M. Kuo, Y. C. Tien, P. C. Shen, Y. W. Kuo, and H. H. Huang, “Steady Augmentation of Anti-Osteoarthritic Actions of Rapamycin by Liposome-Encapsulation in Collaboration With Low-Intensity Pulsed Ultrasound,” International Journal of Nanomedicine 15 (2020): 3771–3790.

[207] C. Kang, E. Jung, H. Hyeon, S. Seon, and D. Lee, “Acid-Activatable Polymeric Curcumin Nanoparticles as Therapeutic Agents for Osteoarthritis,” Nanomedicine 23 (2020): 102104.

[208] G. Q. Teixeira, C. Leite Pereira, F. Castro, et al., “Anti-Inflammatory Chitosan/Poly-γ-glutamic Acid Nanoparticles Control Inflammation While Remodeling Extracellular Matrix in Degenerated Intervertebral Disc,” Acta Biomaterialia 42 (2016): 168–179.

[209] C. Z. Liang, H. Li, Y. Q. Tao, et al., “Dual Delivery for Stem Cell Differentiation Using Dexamethasone and BFGF in/on Polymeric Microspheres as a Cell Carrier for Nucleus Pulposus Regeneration,” Journal of Materials Science: Materials in Medicine 23, no. 4 (2012): 1097–1107.

[210] J. C. Antunes, C. L. Pereira, G. Q. Teixeira, et al., “Poly(γ-Glutamic Acid) and poly(γ-glutamic Acid)-Based Nanocomplexes Enhance Type Ii Collagen Production in Intervertebral Disc,” Journal of Materials Science: Materials in Medicine 28, no. 1 (2017): 6.

[211] X. Yang, L. Jin, L. Yao, F. H. Shen, A. L. Shimer, and X. Li, “Antioxidative Nanofullerol Prevents Intervertebral Disk Degeneration,” International Journal of Nanomedicine 9 (2014): 2419–2430.

[212] C. C. Chang, H. K. Tsou, H. H. Chang, et al., “Runx1 Messenger RNA Delivered by Polyplex Nanomicelles Alleviate Spinal Disc Hydration Loss in a Rat Disc Degeneration Model,” International Journal of Molecular Sciences 23, no. 1 (2022): 565.

[213] C. Y. Lin, S. T. Crowley, S. Uchida, Y. Komaki, K. Kataoka, and K. Itaka, “Treatment of Intervertebral Disk Disease by the Administration of mRNA Encoding a Cartilage-Anabolic Transcription Factor,” Molecular Therapy - Nucleic Acids 16 (2019): 162–171.

[214] H. Tao, Y. Wu, H. Li, et al., “BMP7-Based Functionalized Self-Assembling Peptides for Nucleus Pulposus Tissue Engineering,” ACS Applied Materials & Interfaces 7, no. 31 (2015): 17076–17087.

[215] G. Feng, Z. Zhang, M. Dang, et al., “Injectable Nanofibrous Spongy Microspheres for NR4A1 Plasmid DNA Transfection to Reverse Fibrotic Degeneration and Support Disc Regeneration,” Biomaterials 131 (2017): 86–97.

[216] Y. Gan, S. Li, P. Li, et al., “A Controlled Release Codelivery System of MSCs Encapsulated in Dextran/Gelatin Hydrogel With TGF-Beta3-Loaded Nanoparticles for Nucleus Pulposus Regeneration,” Stem Cells International 2016 (2016): 9042019.

[217] Y. Wang, Y. Zhang, K. Chen, et al., “Injectable Nanostructured Colloidal Gels Resembling Native Nucleus Pulposus as Carriers of Mesenchymal Stem Cells for the Repair of Degenerated Intervertebral Discs,” Materials Science and Engineering: C 128 (2021): 112343.

[218] W. Chen, H. Chen, D. Zheng, et al., “Gene-Hydrogel Microenvironment Regulates Extracellular Matrix Metabolism Balance in Nucleus Pulposus,” Advanced Science (Weinh) 7, no. 1 (2020): 1902099.

[219] H. Chang, F. Cai, Y. Zhang, et al., “Silencing Gene-Engineered Injectable Hydrogel Microsphere for Regulation of Extracellular Matrix Metabolism Balance,” Small Methods 6, no. 4 (2022): e2101201.

[220] Q. Lan, R. Lu, H. Chen, et al., “MMP-13 Enzyme and PH Responsive Theranostic Nanoplatform for Osteoarthritis,” Journal of Nanobiotechnology 18, no. 1 (2020): 117.

[221] M. L. Kang, S. Y. Jeong, and G. I. Im, “Hyaluronic Acid Hydrogel Functionalized With Self-Assembled Micelles of Amphiphilic Pegylated Kartogenin for the Treatment of Osteoarthritis,” Tissue Engineering. Part A 23, no. 13–14 (2017): 630–639.

[222] B. C. Geiger, S. Wang, R. F. Padera, A. J. Grodzinsky, and P. T. Hammond, “Cartilage-Penetrating Nanocarriers Improve Delivery and Efficacy of Growth Factor Treatment of Osteoarthritis,” Science Translational Medicine 10, no. 469 (2018): eaat8800.

[223] S. Lim, S. B. An, M. Jung, et al., “Local Delivery of Senolytic Drug Inhibits Intervertebral Disc Degeneration and Restores Intervertebral Disc Structure,” Advanced Healthcare Materials 11, no. 2 (2022): e2101483.

[224] Z. Guo, W. Su, R. Zhou, et al., “Exosomal MATN3 of Urine-Derived Stem Cells Ameliorates Intervertebral Disc Degeneration by Antisenescence Effects and Promotes NPC Proliferation and ECM Synthesis by Activating TGF-Beta,” Oxidative Medicine and Cellular Longevity 2021 (2021): 5542241.

[225] Q. Zheng, H. Shen, Z. Tong, et al., “A Thermosensitive, Reactive Oxygen Species-Responsive, MR409-encapsulated Hydrogel Ameliorates Disc Degeneration in Rats by Inhibiting the Secretory Autophagy Pathway,” Theranostics 11, no. 1 (2021): 147–163.

[226] H. Yu, Y. Teng, J. Ge, et al., “Isoginkgetin-Loaded Reactive Oxygen Species Scavenging Nanoparticles Ameliorate Intervertebral Disc Degeneration via Enhancing Autophagy in Nucleus Pulposus Cells,” Journal of Nanobiotechnology 21, no. 1 (2023): 99.

[227] H. Huang, X. Liang, S. Li, et al., “Chondrocyte-Targeted Bilirubin/Rapamycin Carrier-Free Nanoparticles Alleviate Oxidative Stress and Modulate Autophagy for Osteoarthritis Therapy,” Journal of Controlled Release 378 (2025): 517–533.

[228] R. R. Banala, S. K. Vemuri, G. H. Dar, et al., “Efficiency of Dual siRNA-Mediated Gene Therapy for Intervertebral Disc Degeneration (Ivdd),” Spine Journal 19, no. 5 (2019): 896–904.

[229] C. Guo, Y. Liu, Z. Zhao, Y. Wu, Q. Kong, and Y. Wang, “Regulating Inflammation and Apoptosis: A Smart Microgel Gene Delivery System for Repairing Degenerative Nucleus Pulposus,” Journal of Controlled Release 365 (2024): 1004–1018.

[230] A. Karim, R. Qaisar, S. Suresh, J. Jagal, and M. Rawas-Qalaji, “Nanoparticle-Delivered Quercetin Exhibits Enhanced Efficacy in Eliminating Iron-Overloaded Senescent Chondrocytes,” Nanomedicine 19, no. 26 (2024): 2159–2170.

[231] H. Wang, Z. Li, J. Liu, et al., “Nanozyme-Enhanced Injectable Hyaluronic Acid-Based Hydrogel for the Treatment of Osteoarthritis,” International Journal of Biological Macromolecules 282, no. Pt 2 (2024): 136819.

[232] H. Xing, Z. Zhang, Q. Mao, et al., “Injectable Exosome-Functionalized Extracellular Matrix Hydrogel for Metabolism Balance and Pyroptosis Regulation in Intervertebral Disc Degeneration,” Journal of Nanobiotechnology 19, no. 1 (2021): 264.

[233] K. Sun, C. Yan, X. Dai, et al., “Catalytic Nanodots-Driven Pyroptosis Suppression in Nucleus Pulposus for Antioxidant Intervention of Intervertebral Disc Degeneration,” Advanced Materials 36, no. 19 (2024): e2313248.

[234] A. Sarkar, E. Carvalho, A. A. D'Souza, and R. Banerjee, “Liposome-Encapsulated Fish Oil Protein-Tagged Gold Nanoparticles for Intra-Articular Therapy in Osteoarthritis,” Nanomedicine 14, no. 7 (2019): 871–887.

[235] X. Yu, H. Xu, Q. Liu, et al., “circ_0072464 Shuttled by Bone Mesenchymal Stem Cell-Secreted Extracellular Vesicles Inhibits Nucleus Pulposus Cell Ferroptosis to Relieve Intervertebral Disc Degeneration,” Oxidative Medicine and Cellular Longevity 2022 (2022): 2948090.

[236] X. Yang, Y. Chen, J. Guo, et al., “Polydopamine Nanoparticles Targeting Ferroptosis Mitigate Intervertebral Disc Degeneration via Reactive Oxygen Species Depletion, Iron Ions Chelation, and GPX4 Ubiquitination Suppression,” Advanced Science (Weinh) 10, no. 13 (2023): e2207216.

[237] Y. Xu, F. Cai, Y. Zhou, et al., “Magnetically Attracting Hydrogel Reshapes Iron Metabolism for Tissue Repair,” Science Advances 10, no. 33 (2024): o7249.

[238] J. Feng, X. Deng, P. Hao, et al., “Intra-Articular Injection of Platinum Nanozyme-Loaded Silk Fibroin/Pullulan Hydrogels Relieves Osteoarthritis Through Ros Scavenging and Ferroptosis Suppression,” International Journal of Biological Macromolecules 280, no. pt 2 (2024): 135863.

[239] J. Wang, R. Wu, Z. Liu, et al., “Core–Shell Structured Nanozyme With PDA-Mediated Enhanced Antioxidant Efficiency to Treat Early Intervertebral Disc Degeneration,” ACS Applied Materials & Interfaces 16, no. 4 (2024): 5103–5119.

[240] W. Bu, Y. Shi, X. Huang, et al., “Rescue of Nucleus Pulposus Cells From an Oxidative Stress Microenvironment via Glutathione-Derived Carbon Dots to Alleviate Intervertebral Disc Degeneration,” Journal of Nanobiotechnology 22, no. 1 (2024): 412.

[241] S. Wu, Y. Shi, L. Jiang, et al., “N-Acetylcysteine-Derived Carbon Dots for Free Radical Scavenging in Intervertebral Disc Degeneration,” Advanced Healthcare Materials 12, no. 24 (2023): e2300533.

[242] T. Zhou, X. Yang, Z. Chen, et al., “Prussian Blue Nanoparticles Stabilize SOD1 From Ubiquitination-Proteasome Degradation to Rescue Intervertebral Disc Degeneration,” Advanced Science 9, no. 10 (2022): e2105466.

[243] L. Zhu, Y. Yang, Z. Yan, et al., “Controlled Release of TGF-beta3 for Effective Local Endogenous Repair in IDD Using Rat Model,” International Journal of Nanomedicine 17 (2022): 2079–2096.

[244] J. Shen, A. Chen, Z. Cai, et al., “Exhausted Local Lactate Accumulation via Injectable Nanozyme-Functionalized Hydrogel Microsphere for Inflammation Relief and Tissue Regeneration,” Bioactive Materials 12 (2022): 153–168.

[245] J. Bai, Y. Zhang, Q. Fan, et al., “Reactive Oxygen Species-Scavenging Scaffold With Rapamycin for Treatment of Intervertebral Disk Degeneration,” Advanced Healthcare Materials 9, no. 3 (2020): e1901186.

[246] W. Hou, C. Ye, M. Chen, et al., “Excavating Bioactivities of Nanozyme to Remodel Microenvironment for Protecting Chondrocytes and Delaying Osteoarthritis,” Bioactive Materials 6, no. 8 (2021): 2439–2451.

[247] B. Crivelli, E. Bari, S. Perteghella, et al., “Silk Fibroin Nanoparticles for Celecoxib and Curcumin Delivery: ROS-Scavenging and Anti-Inflammatory Activities in an In Vitro Model of Osteoarthritis,” European Journal of Pharmaceutics and Biopharmaceutics 137 (2019): 37–45.

[248] H. J. Shin, H. Park, N. Shin, et al., “p47phox Sirna-Loaded Plga Nanoparticles Suppress ROS/Oxidative Stress-Induced Chondrocyte Damage in Osteoarthritis,” Polymers (Basel) 12, no. 2 (2020): 443.

[249] R. Deng, R. Zhao, Z. Zhang, et al., “Chondrocyte Membrane–Coated Nanoparticles Promote Drug Retention and Halt Cartilage Damage in Rat and Canine Osteoarthritis,” Science Translational Medicine 16, no. 735 (2024): h9751.

[250] N. Bergknut, J. P. H. J. Rutges, H. J. C. Kranenburg, et al., “The Dog as an Animal Model for Intervertebral Disc Degeneration?,” Spine 37, no. 5 (2012): 351–358.

[251] Q. Liu, Y. Zhao, H. Zhou, and C. Chen, “Ferroptosis: Challenges and Opportunities for Nanomaterials in Cancer Therapy,” Regenerative Biomaterials 10 (2023): d4.

[252] P. Joyce, C. J. Allen, M. J. Alonso, et al., “A Translational Framework to DELIVER Nanomedicines to the Clinic,” Nature Nanotechnology 19, no. 11 (2024): 1597–1611.

[253] H. Zhang, D. Cai, and X. Bai, “Macrophages Regulate the Progression of Osteoarthritis,” Osteoarthritis and Cartilage 28, no. 5 (2020): 555–561.

[254] X. Chen, X. Li, Y. Wang, and S. Lu, “Relation of Lumbar Intervertebral Disc Height and Severity of Disc Degeneration Based on Pfirrmann Scores,” Heliyon 9, no. 10 (2023): e20764.

RIGHTS & PERMISSIONS

2025 The Author(s). MedComm – Biomaterials and Applications published by John Wiley & Sons Australia, Ltd on behalf of Sichuan International Medical Exchange & Promotion Association (SCIMEA).