Interfacial Engineering of Pillararene-Modified Ceria Nanoparticles for Regulable Enhanced Sonodynamic Therapy

Abstract

Sonodynamic therapy (SDT) has emerged as an advanced technology for treatment of malignant tumors. Many organic and inorganic sonosensitizers have been reported but they still have the respective limitations. Constructing the materials to integrate the superiorities of organic and inorganic sonosensitizers is expected to be a good method to enhance the efficiency of SDT. Herein, we report an intelligent sonosensitizer (TPA–OS⊂CP5@CeO_x), integrating the organic (TPA–OS) and inorganic sonosensitizers (CP5@CeO_x) via host–guest interaction. The modification of carboxyl-pillar[5]arene (CP5) on CeO_x constructs the supramolecular interface by coupling of CP5 and oxygen vacancies. The band gap of CeO_x is reduced and the ratio of Ce⁴⁺/Ce³⁺ is increased to regulate tumor microenvironment. Thus, the SDT performance of CP5@CeO_x can be improved. Furthermore, the synergistic effect of TPA–OS with aggregation-induced emission can further regulate and enhance the SDT efficiency. The cellular experiments demonstrate that TPA–OS⊂CP5@CeO_x exhibits the synergistic therapeutic effect in double organelle of lysosome and mitochondria. The in vivo experiments suggest TPA–OS⊂CP5@CeO_x has imaging-guided enhanced SDT performance to achieve tumor inhibition. This study contributes to the construction of novel intelligent sonosensitizers, indicating that supramolecular interface engineering is promising to realize the customized treatments with minimal side effects.

Keywords

ceria oxide / interfacial interaction / pillararenes / regulation / sonodynamic therapy

References

[1] H. Sung, J. Ferlay, R. L. Siegel, et al., “Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries,” Ca: A Cancer Journal for Clinicians 71 (2021): 209-249.

[2] J. J. Shi, P. W. Kantoff, R. Wooster, and O. C. Farokhzad, “Cancer Nanomedicine: Progress, Challenges and Opportunities,” Nature Reviews Cancer 17 (2017): 20-37.

[3] H. Huang, Z. Y. Wang, L. Chen, H. Yu, and Y. Chen, “Catalytic Biomaterials and Nanomedicines With Exogenous and Endogenous Activations,” Advanced Healthcare Materials 12 (2023): 2201607.

[4] R. He, Y. C. Wang, X. Y. Wang, et al., “Facile Synthesis of Pentacle Gold-Copper Alloy Nanocrystals and Their Plasmonic and Catalytic Properties,” Nature Communications 5 (2014): 4327.

[5] J. Chen, S. K. Li, Z. Y. Wang, et al., “Synthesis of an AIEgen Functionalized Cucurbit[7]Uril for Subcellular Bioimaging and Synergistic Photodynamic Therapy and Supramolecular Chemotherapy,” Chemical Science 12 (2021): 7727-7734.

[6] Z. Wang, Z. Yang, S. Li, et al., “Light-Directed Microalgae Micromotor With Supramolecular Backpacks for Photodynamic Therapy,” Advanced Functional Materials 35 (2025): 2411070.

[7] L. Wang, G. Z. Li, L. Cao, et al., “An Ultrasound-driven Immune-boosting Molecular Machine for Systemic Tumor Suppression,” Science Advances 7 (2021): eabj4796.

[8] C. Zhang and K. Y. Pu, “Organic Sonodynamic Materials for Combination Cancer Immunotherapy,” Advanced Materials 35 (2023): 2303059.

[9] X. Q. Qian, Y. Y. Zheng, and Y. Chen, “Micro/Nanoparticle-Augmented Sonodynamic Therapy (SDT): Breaking the Depth Shallow of Photoactivation,” Advanced Materials 28 (2016): 8097-8129.

[10] S. Liang, X. R. Deng, P. A. Ma, Z. Y. Cheng, and J. Lin, “Recent Advances in Nanomaterial-Assisted Combinational Sonodynamic Cancer Therapy,” Advanced Materials 32 (2020): 2003214.

[11] V. G. Deepagan, D. G. You, W. Um, et al., “Long-Circulating Au-TiO₂ Nanocomposite as a Sonosensitizer for ROS-Mediated Eradication of Cancer,” Nano Letters 16 (2016): 6257-6264.

[12] L. H. Sun, P. Wang, J. X. Zhang, et al., “Design and Application of Inorganic Nanoparticles for Sonodynamic Cancer Therapy,” Biomaterials Science 9 (2021): 1945-1960.

[13] C. H. Dong, H. Hu, L. P. Sun, and Y. Chen, “Inorganic Chemoreactive Nanosonosensitzers With Unique Physiochemical Properties and Structural Features for Versatile Sonodynamic Nanotherapies,” Biomedical Materials 16 (2021): 032006.

[14] X. Pang, Q. C. Xiao, Y. Cheng, et al., “Bacteria-Responsive Nanoliposomes as Smart Sonotheranostics for Multidrug Resistant Bacterial Infections,” ACS Nano 13 (2019): 2427-2438.

[15] S. A. Liu, K. K. Dou, B. Liu, M. L. Pang, P. A. Ma, and J. Lin, “Construction of Multiform Hollow-Structured Covalent Organic Frameworks via a Facile and Universal Strategy for Enhanced Sonodynamic Cancer Therapy,” Angewandte Chemie International Edition 62 (2023): e202301831.

[16] Z. Gong, D. Hou, Y. Xu, et al., “Enhancing SDT Efficacy of Doxorubicin-Loaded Sonosensitizer Micelles to Overcome Resistance of Cancer Therapy by Optimizing Acoustic Parameters,” Aggregate (2025): e70005, https://doi.org/10.1002/agt2.70005.

[17] Y. J. Wang, F. Gong, Z. H. Han, et al., “Oxygen-Deficient Molybdenum Oxide Nanosensitizers for Ultrasound-Enhanced Cancer Metalloimmunotherapy,” Angewandte Chemie International Edition 62 (2023): e202215467.

[18] Z. Yang, M. Yuan, B. Liu, et al., “Conferring BiVO₄ Nanorods With Oxygen Vacancies to Realize Enhanced Sonodynamic Cancer Therapy,” Angewandte Chemie International Edition 61 (2022): e202209484.

[19] Y. M. Zhao, J. H. Liu, M. T. He, et al., “Platinum-Titania Schottky Junction as Nanosonosensitizer, Glucose Scavenger, and Tumor Microenvironment-Modulator for Promoted Cancer Treatment,” ACS Nano 16 (2022): 12118-12133.

[20] G. Y. Feng, H. Huang, M. Zhang, et al., “Single Atom Iron-Doped Graphic-Phase C₃ N₄ Semiconductor Nanosheets for Augmented Sonodynamic Melanoma Therapy Synergy With Endowed Chemodynamic Effect,” Advanced Science 10 (2023): 2302579.

[21] C. Gao, C. H. T. Kwong, Q. F. Wang, et al., “Conjugation of Macrophage-Mimetic Microalgae and Liposome for Antitumor Sonodynamic Immunotherapy via Hypoxia Alleviation and Autophagy Inhibition,” ACS Nano 17 (2023): 4034-4049.

[22] Y. Y. Wang, Y. C. Liu, H. W. Sun, and D. S. Guo, “Type I Photodynamic Therapy by Organic-inorganic Hybrid Materials: From Strategies to Applications,” Coordination Chemistry Reviews 395 (2019): 46-62.

[23] Y. Zhang, S. Zhao, J. Feng, et al., “Unraveling the Physical Chemistry and Materials Science of CeO₂-Based Nanostructures,” Chem 7 (2021): 2022-2059.

[24] C. F. Wang, J. Lei, C. Y. Mao, et al., “Defective S-TiO_2−x/CeO₂ Heterojunction for Mutual Reinforcing Chemodynamic/Sonocatalytic Antibacterial Therapy and Sonoelectric/Ion-Activated Bone Regeneration,” Advanced Functional Materials 33 (2023): 2306493.

[25] C. Xu and X. G. Qu, “Cerium Oxide Nanoparticle: A Remarkably Versatile Rare Earth Nanomaterial for Biological Applications,” Npg Asia Materials 6 (2014): e90.

[26] V. Baldim, F. Bedioui, N. Mignet, I. Margaill, and J. F. Berret, “The Enzyme-Like Catalytic Activity of Cerium Oxide Nanoparticles and Its Dependency on Ce³⁺ Surface Area Concentration,” Nanoscale 10 (2018): 6971-6980.

[27] C. Yao, W. X. Wang, P. Y. Wang, M. Y. Zhao, X. M. Li, and F. Zhang, “Near-Infrared Upconversion Mesoporous Cerium Oxide Hollow Biophotocatalyst for Concurrent pH-/H₂O₂-Responsive O₂-Evolving Synergetic Cancer Therapy,” Advanced Materials 30 (2018): 1704833.

[28] Y. P. Zhu, C. X. Guo, Y. Zheng, and S. Z. Qiao, “Surface and Interface Engineering of Noble-Metal-Free Electrocatalysts for Efficient Energy Conversion Processes,” Accounts of Chemical Research 50 (2017): 915-923.

[29] Y. Peng, Q. M. Liu, B. Z. Lu, et al., “Organically Capped Iridium Nanoparticles as High-Performance Bifunctional Electrocatalysts for Full Water Splitting in both Acidic and Alkaline Media: Impacts of Metal-Ligand Interfacial Interactions,” ACS Catalysis 11 (2021): 1179-1188.

[30] Y. Song, S. Lee, Y. Ko, et al., “Charge-Transfer Effects of Organic Ligands on Energy Storage Performance of Oxide Nanoparticle-Based Electrodes,” Advanced Functional Materials 32 (2022): 2106438.

[31] X. P. Liu, X. H. Wang, C. X. Mao, et al., “Ligand-Hybridization Activates Lattice-Hydroxyl-Groups of NiCo(OH)_X Nanowires for Efficient Electrosynthesis,” Angewandte Chemie International Edition 63 (2024): e202408109.

[32] Z. T. Li, J. Yang, G. C. Yu, J. M. He, Z. Abliz, and F. H. Huang, “Water-Soluble Pillar[7]Arene: Synthesis, pH-Controlled Complexation With Paraquat, and Application in Constructing Supramolecular Vesicles,” Organic Letters 16 (2014): 2066-2069.

[33] N. Song, Z. J. Zhang, P. Y. Liu, et al., “Pillar[5]Arene-Modified Gold Nanorods as Nanocarriers for Multi-Modal Imaging-Guided Synergistic Photodynamic-Photothermal Therapy,” Advanced Functional Materials 31 (2021): 2009924.

[34] M. A. H. Muhammed, L. K. Cruz, A. H. Emwas, et al., “Pillar[5]Arene-Stabilized Silver Nanoclusters: Extraordinary Stability and Luminescence Enhancement Induced by Host-Guest Interactions,” Angewandte Chemie International Edition 58 (2019): 15665-15670.

[35] Q. L. Li, Y. Sun, L. Ren, et al., “Supramolecular Nanosystem Based on Pillararene-Capped CuS Nanoparticles for Targeted Chemo-Photothermal Therapy,” ACS Applied Materials & Interfaces 10 (2018): 29314-29324.

[36] H. Zhang, J. R. Wu, X. Wang, et al., “One-pot Solvothermal Synthesis of Carboxylatopillar[5]Arene-modified Fe₃O₄ Magnetic Nanoparticles for Ultrafast Separation of Cationic Dyes,” Dyes Pigments 162 (2019): 512-516.

[37] H. H. Li, R. Y. Wei, G. H. Yan, et al., “Smart Self-Assembled Nanosystem Based on Water-Soluble Pillararene and Rare-Earth-Doped Upconversion Nanoparticles for pH-Responsive Drug Delivery,” ACS Applied Materials & Interfaces 10 (2018): 4910-4920.

[38] X. Wang, L. L. Tan, X. Li, et al., “Smart Mesoporous Silica Nanoparticles Gated by Pillararene-modified Gold Nanoparticles for on-Demand Cargo Release,” Chemical Communications 52 (2016): 13775-13778.

[39] G. C. Yu, K. C. Jie, and F. H. Huang, “Supramolecular Amphiphiles Based on Host-Guest Molecular Recognition Motifs,” Chemical Reviews 115 (2015): 7240-7303.

[40] H. An, Y. Hu, N. Song, et al., “Two-dimensional Heterostructures Built From Ultrathin CeO₂ Nanosheet Surface-coordinated and Confined Metal-organic Frameworks With Enhanced Stability and Catalytic Performance,” Chemical Science 13 (2022): 3035-3044.

[41] K. K. Patra, Z. Liu, H. J. Lee, et al., “Boosting Electrochemical CO₂ Reduction to Methane via Tuning Oxygen Vacancy Concentration and Surface Termination on a Copper/Ceria Catalyst,” ACS Catalysis 12 (2022): 10973-10983.

[42] N. Yadav and S. Singh, “Polyoxometalate-Mediated Vacancy-Engineered Cerium Oxide Nanoparticles Exhibiting Controlled Biological Enzyme-Mimicking Activities,” Inorganic Chemistry 60 (2021): 7475-7489.

[43] B. A. Reddy, A. Khan, Y. Yamada, T. Kobayashi, S. Loridant, and J. C. Volta, “Surface Characterization of CeO₂/SiO₂ and V₂O₅/CeO₂/SiO₂ Catalysts by Raman, XPS, and Other Techniques,” Journal of Physical Chemistry B 106 (2002): 10964-10972.

[44] Y. Lykhach, S. M. Kozlov, T. Skála, et al., “Counting Electrons on Supported Nanoparticles,” Nature Materials 15 (2016): 284-288.

[45] S. C. Rood, O. Pastor-Algaba, A. Tosca-Princep, et al., “Synergistic Effect of Simultaneous Doping of Ceria Nanorods With Cu and Cr on CO Oxidation and NO Reduction,” Chemistry - A European Journal 27 (2021): 2165-2174.

[46] J. A. Fortner and E. C. Buck, “The Chemistry of the Light Rare-earth Elements as Determined by Electron Energy Loss Spectroscopy,” Applied Physics Letters 68 (1996): 3817-3819.

[47] L. Shao, Y. Pan, B. Hua, et al., “Constructing Adaptive Photosensitizers via Supramolecular Modification Based on Pillararene Host-Guest Interactions,” Angewandte Chemie International Edition 59 (2020): 11779-11783.

[48] J. J. Kong, Z. W. Xiang, G. Y. Li, and T. C. An, “Introduce Oxygen Vacancies Into CeO₂ Catalyst for Enhanced Coke Resistance During Photothermocatalytic Oxidation of Typical VOCs,” Applied Catalysis B: Environment and Energy 269 (2020): 118755.

[49] R. T. Chen, F. T. Fan, T. Dittrich, and C. Li, “Imaging Photogenerated Charge Carriers on Surfaces and Interfaces of Photocatalysts With Surface Photovoltage Microscopy,” Chemical Society Reviews 47 (2018): 8238-8262.

[50] X. F. Jia, Y. Lu, K. R. Du, et al., “Interfacial Mediation by Sn and S Vacancies of p -SnS/n -ZnIn₂S₄ for Enhancing Photocatalytic Hydrogen Evolution With New Scheme of Type-I Heterojunction,” Advanced Functional Materials 33 (2023): 2304072.

[51] S. Li, C. Gao, H. Yu, et al., “Vinylene-Linked Donor-π-Acceptor Metal-Covalent Organic Framework for Enhanced Photocatalytic CO₂ Reduction,” Angewandte Chemie International Edition 63 (2024): e202409925.

[52] B. F. Chen, Z. Y. Meng, P. Ouyang, et al., “S^2- doping Inducing Self-adapting Dual Anion Defects in ZnSn(OH)₆ for Highly Efficient Photoactivity,” Applied Catalysis B: Environment and Energy 338 (2023): 123093.

[53] S. M. Dong, Y. S. Dong, B. Liu, et al., “Guiding Transition Metal-Doped Hollow Cerium Tandem Nanozymes With Elaborately Regulated Multi-Enzymatic Activities for Intensive Chemodynamic Therapy,” Advanced Materials 34 (2022): 2107054.

[54] J. VandeVondele, M. Krack, F. Mohamed, M. Parrinello, T. Chassaing, and J. Hutter, “Quickstep: Fast and Accurate Density Functional Calculations Using a Mixed Gaussian and Plane Waves Approach,” Computer Physics Communications 167 (2005): 103-128.

[55] S. Goedecker, M. Teter, and J. Hutter, “Separable Dual-Space Gaussian Pseudopotentials,” Physical Review B 54 (1996): 1703-1710.

[56] C. Hartwigsen, S. Goedecker, and J. Hutter, “Relativistic Separable Dual-Space Gaussian Pseudopotentials From H to Rn,” Physical Review B 58 (1998): 3641-3662.

[57] J. VandeVondele and J. Hutter, “Gaussian Basis Sets for Accurate Calculations on Molecular Systems in Gas and Condensed Phases,” Journal of Chemical Physics 127 (2007): 114105.

[58] J. P. Perdew, K. Burke, and M. Ernzerhof, “Generalized Gradient Approximation Made Simple,” Physical Review Letter 77 (1996): 3865-3868.

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