Biomimetic Thalidomide Nanoparticles: Targeted and Sustained Therapeutic Strategy for Oxygen-Induced Retinopathy

Abstract

Retinal neovascularization (RNV) drives dual pathological cascades: structural destruction characterized by intraretinal/vitreous hemorrhages and tractional retinal detachment, alongside functional decline marked by progressive neurodegeneration and irreversible vision loss. Current clinical interventions for RNV face critical limitations in targeting specificity and therapeutic durability. To address this, we engineer magnesium acetyl taurate/thalidomide co-assembled nanoparticles (MT NPs) via Super-stable Pure Nanomedicine Formulation Technology (SPFT), constructing solvent-free, coordination-driven nanostructures with dual-drug loading. The MT NPs are further coated with transferrin-modified cell membrane vesicles (Tfm) to form targeted nanocomposites (Tfm@MT NPs). In oxygen-induced retinopathy (OIR) mouse models, Tfm@MT NPs demonstrated: (1) specific targeting to pathological vascular endothelia and retinal ganglion cells (RGCs) via transferrin receptor-mediated uptake, (2) sustained drug release exceeding 10 days, and (3) potent therapeutic effects in restoring visual functions. This study establishes a safe and effective targeted nanotherapeutic strategy for RNV, with significant translational potential for retinopathy treatment.

Keywords

magnesium acetyl taurate / nanoparticle / oxygen-induced retinopathy / self-assembly / thalidomide / transferrin

References

[1] P. A. Campochiaro, “Molecular Pathogenesis of Retinal and Choroidal Vascular Diseases,” Progress in Retinal and Eye Research 129 (2015): 1389–1401.

[2] A. R. Fielder, G. E. Quinn, P. K. Shah, B. A. Darlow, and N. Marlow, “Retinopathy of Prematurity Comes Full Circle,” Archives of Disease in Childhood Fetal and Neonatal Edition 110 (2024): 8–9.

[3] O. Dammann, M. E. Hartnett, and A. Stahl, “Retinopathy of Prematurity,” Developmental Medicine and Child Neurology 65 (2023): 625–631.

[4] M. Sanz, A. Marco Del Castillo, S. Jepsen, et al., “Periodontitis and Cardiovascular Diseases: Consensus Report,” Journal of Clinical Periodontology 47 (2020): 268–288.

[5] X. Ma, Y. Cui, M. Zhang, Q. Lyu, and J. Zhao, “A Multifunctional Nanodrug Co-Delivering VEGF-siRNA and Dexamethasone for Synergistic Therapy in Ocular Neovascular Diseases,” International Journal of Nanomedicine 19 (2024): 12369–12387.

[6] N. Zhao, X. Gui, Q. Fang, et al., “Graphene Quantum Dots Rescue Angiogenic Retinopathy via Blocking STAT3/Periostin/ERK Signaling,” Journal of Nanobiotechnology 20 (2022): 174.

[7] A. M. Elbedwehy, J. Wu, H. K. Na, et al., “ROS-Responsive Charge Reversal Mesoporous Silica Nanoparticles as Promising Drug Delivery System for Neovascular Retinal Diseases,” Journal of Controlled Release 373 (2024): 224–239.

[8] R. Fan, L. Su, H. Zhang, et al., “Enhanced Therapeutic Effect of PEDF-Loaded Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Against Oxygen-Induced Retinopathy Through Increased Stability and Penetrability of PEDF,” Journal of Nanobiotechnology 21 (2023): 327.

[9] Z. Meng, B. Fu, Z. Yang, et al., “Polydopamine-Coated Thalidomide Nanocrystals Promote DSS-Induced Murine Colitis Recovery Through Macrophage M2 Polarization Together With the Synergistic Anti-Inflammatory and Anti-Angiogenic Effects,” International Journal of Pharmaceutics 630 (2023): 122376.

[10] R. R. Mabrouk, A. E. Abdallah, H. A. Mahdy, et al., “Design. Synthesis, and Biological Evaluation of New Potential Unusual Modified Anticancer Immunomodulators for Possible Non-Teratogenic Quinazoline-Based Thalidomide Analogs,” International Journal of Molecular Sciences 24 (2023): 12416.

[11] N. M. Tawfik, M. S. Teiama, S. S. Iskandar, A. Osman, and S. F. Hammad, “A Novel Nanoemulsion Formula for an Improved Delivery of a Thalidomide Analogue to Triple-Negative Breast Cancer; Synthesis, Formulation, Characterization and Molecular Studies,” International Journal of Nanomedicine 18 (2023): 1219–1243.

[12] M. E. Franks, G. R. Macpherson, and W. D. Figg, “Thalidomide,” Lancet 363 (2004): 1802–1811.

[13] G. B. Rodrigues, G. F. Passos, G. Di Giunta, et al., “Preventive and Therapeutic Anti-Inflammatory Effects of Systemic and Topical Thalidomide on Endotoxin-Induced Uveitis in Rats,” Experimental Eye Research 84 (2007): 553–560.

[14] Y. Xu, S. Huang, S. Zhou, et al., “Iron Chelator Deferiprone Restores Iron Homeostasis and Inhibits Retinal Neovascularization in Experimental Neovascular Age-Related Macular Degeneration,” Investigative Ophthalmology & Visual Science 65 (2024): 5.

[15] J. McGaunn and J. A. Baur, “Taurine Linked With Healthy Aging,” Science 380 (2023): 1010–1011.

[16] L. Dominguez, N. Veronese, and M. Barbagallo, “Magnesium and Hypertension in Old Age,” Nutrients 13 (2020): 139.

[17] A. J. A. Jafri, N. N. N. Arfuzir, L. Lambuk, et al., “Protective Effect of Magnesium Acetyltaurate Against NMDA-Induced Retinal Damage Involves Restoration of Minerals and Trace Elements Homeostasis,” Journal of Trace Elements in Medicine and Biology 39 (2017): 147–154.

[18] Y. Zhang, H. Cheng, H. Chen, et al., “A Pure nanoICG-Based Homogeneous Lipiodol Formulation: Toward Precise Surgical Navigation of Primary Liver Cancer After Long-Term Transcatheter Arterial Embolization,” European Journal of Nuclear Medicine and Molecular Imaging 49 (2022): 2605–2617.

[19] H. Wu, J. Ye, M. Zhang, et al., “A SU6668 Pure Nanoparticle-Based Eyedrops: Toward Its High Drug Accumulation and Long-Time Treatment for Corneal Neovascularization,” Journal of Nanobiotechnology 22 (2024): 290.

[20] X. Shi, D. Xu, H. Cheng, C. Chu, and G. Liu, “Recent Advances in Interventional Fluorescence Imaging: Toward the Precise Visualization of Transarterial Mini-Invasive Delivery Systems,” Accounts of Materials Research 4 (2023): 251–263.

[21] H. Zhu, J. Ye, Y. Wu, et al., “A Synergistic Therapy with Antioxidant and Anti-VEGF: Toward Its Safe and Effective Elimination for Corneal Neovascularization,” Advanced Healthcare Materials 13 (2023): e2302192.

[22] J. Ye, Y. Cheng, X. Wen, et al., “Biomimetic Nanocomplex Based Corneal Neovascularization Theranostics,” Journal of Controlled Release 374 (2024): 50–60.

[23] C. Li, C. Xiao, H. Tao, and X. Tang, “Research Progress of Iron Metabolism in Retinal Diseases,” Advances in Ophthalmology Practice and Research 3 (2023): 93–100.

[24] M. Y. Ho, S. Liu, and B. Xing, “Bacteria Extracellular Vesicle as Nanopharmaceuticals for Versatile Biomedical Potential,” Nano Convergence 11 (2024): 28.

[25] J. Deng, Q. Wang, L. Zhang, et al., “Metallogenetic Model of Jiaodong-Type Gold Deposits, Eastern China,” Science China Earth Sciences 66 (2023): 2287–2310.

[26] X. Ai, M. Hu, Z. Wang, et al., “Recent Advances of Membrane-Cloaked Nanoplatforms for Biomedical Applications,” Bioconjugate Chemistry 29 (2018): 838–851.

[27] S. Bai, Z. Lu, Y. Jiang, et al., “Nanotransferrin-Based Programmable Catalysis Mediates Three-Pronged Induction of Oxidative Stress to Enhance Cancer Immunotherapy,” ACS Nano 16 (2022): 997–1012.

[28] L. Y. Su, Y. Tian, Q. Zheng, et al., “Anti-Tumor Immunotherapy Using Engineered Bacterial Outer Membrane Vesicles Fused to Lysosome-Targeting Chimeras Mediated by Transferrin Receptor,” Cell Chemical Biology 31 (2024): 1219–1230.e5.

[29] P. T. Gomme, K. B. McCann, and J. Bertolini, “Transferrin: Structure, Function and Potential Therapeutic Actions,” Drug Disco Today 10 (2005): 267–273.

[30] S. L. Calzi, L. C. Shaw, L. Moldovan, W. C. Shelley, et al., “Progenitor Cell Combination Normalizes Retinal Vascular Development in the Oxygen-Induced Retinopathy (OIR) Model,” JCI Insight 4 (2019): e129224.

[31] X. Ma, W. Wu, W. Liang, Y. Takahashi, J. Cai, and J. X. Ma, “Modulation of cGAS-STING Signaling by PPARα in a Mouse Model of Ischemia-Induced Retinopathy,” Proceedings of the National Academy of Sciences of USA 119 (2022): e2208934119.

[32] P. He, S. Yi, J. Zhang, et al., “Carrier-Free 5-Fu Nanoparticle-Mediated Domestication Therapy for Scar Treatment: A Preclinical and First-in-Human Study,” Chemical Engineering Journal 475 (2023): 146061.

[33] Y. Ma, Z. Zhang, X. Cao, et al., “Semaphorin 6A Phase Separation Sustains a Histone Lactylation-Dependent Lactate Buildup in Pathological Angiogenesis,” Proceedings of the National Academy of Sciences of USA 122 (2025): e2423677122.

[34] Y. Jin, X. Zhou, L. Chen, et al., “Framework Nucleic Acids Loaded With Quercetin: Protecting Retinal Neurovascular Unit via the Protein Kinase B/Heme Oxygenase-1 Pathway,” ACS Nano 18 (2024): 26076–26087.

[35] J. Muñoz-Sánchez and M. E. Chánez-Cárdenas, “The Use of Cobalt Chloride as a Chemical Hypoxia Model,” Journal of Applied Toxicology 39 (2019): 556–570.

[36] T. Yang, J. Zhang, Q. Hao, S. Ma, and X. Cheng, “Efficacy and Safety of Aflibercept and Ranibizumab in the Treatment of Retinopathy of Prematurity,” Clinical Therapeutics 46 (2024): 773–777.

[37] E. Chang, A. S. Josan, R. Purohit, C. K. Patel, and K. Xue, “A Network Meta-Analysis of Retreatment Rates Following Bevacizumab, Ranibizumab, Aflibercept, and Laser for Retinopathy of Prematurity,” Ophthalmology 129 (2022): 1389–1401.

[38] A. Ortiz-Seller, P. Martorell, H. Barranco, I. Pascual-Camps, E. Morcillo, and J. L. Ortiz, “Comparison of Different Agents and Doses of Anti-Vascular Endothelial Growth Factors (Aflibercept, Bevacizumab, Conbercept, Ranibizumab) Versus Laser for Retinopathy of Prematurity: A Network Meta-Analysis,” Survey of Ophthalmology 69 (2024): 585–605.

[39] Y. Xu, X. Lu, Y. Hu, et al., “Melatonin Attenuated Retinal Neovascularization and Neuroglial Dysfunction by Inhibition of HIF-1α-VEGF Pathway in Oxygen-Induced Retinopathy Mice,” Journal of Pineal Research 64 (2018): e12473.

[40] L. Tan, D. L. Ringach, and J. T. Trachtenberg, “The Development of Receptive Field Tuning Properties in Mouse Binocular Primary Visual Cortex,” Journal of Neuroscience 42 (2022): 3546–3556.

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2025 The Author(s). Aggregate published by SCUT, AIEI, and John Wiley & Sons Australia, Ltd.