Facile fabrication of polyphenolic flavonoids nanoparticles via one-pot assembly for treatment of spinal cord injury
(
), Linrui Cai3 ()Graphical Abstract
Abstract
Polyphenolic flavonoids have shown promising therapeutic effects in spinal cord injury (SCI) due to their outstanding antioxidative and anti-inflammatory functions. However, some of their inherent physicochemical properties such as poor water solubility, low stability and bioavailability, and strong biological metabolism, severely limit the clinical applications. Moreover, the current polyphenolic flavonoid delivery systems have some problems such as sophisticated preparation processes, low yields, high cost, and lack of targeted traceless release. To address those critical issues, we have proposed a general, facile and robust delivery strategy to prepare functional nanoparticles (NPs) through one-pot assembly of polyphenolic flavonoids and their molecular adaptors. Polyethylene glycol (PEG), one of the most widely used biocompatible polymers, and o-aldehyde phenylboric acid, a kind of small molecule adapters, were selected to form NPs with flavonoids. In addition to excellent anti-inflammatory and antioxidant properties, resulting NPs have also demonstrated possess the targeted enrichment of high reactive oxygen species levels in damaged areas and long-term blood circulation stability, which worked well for SCI therapy. This strategy takes the most commonly used PEG as an example, which can be further applied to many other types of hydrophilic polymers with amino groups, such as polysaccharides, peptides and proteins etc.
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References
Shin, Y.; Kim, M.; Lee, E. S.; Lim, C.; Oh, K. T. RNA-Seq-guided triple-combination nano-system of gold nanocluster, quercetin, and docetaxel for ultimate synergistic photothermal-chemotherapy against MDR tumor. Nano Today 2023, 50, 101862.
Tang, N.; Ding, Z.; Zhang, S. Q.; Luo, D. F.; Liu, X. C.; Bao, X. F.; Liu, C. Y.; Liu, Z. Nanoassemblies derived from natural flavonoid compounds as new antioxidant oral preparations for targeted inflammatory bowel disease therapy. Adv. Funct. Mater. 2023, 33, 2305133.
Sun, M.; Peng, S. Q.; Zhao, C. L.; Huang, J. X.; Xia, J. Y.; Ye, D.; Dou, X. Q.; Hou, W. Y.; Feng, C. L. Herb-functionalized chronic wound dressings for enhancing biological functions: Multiple flavonoids coordination driven strategy. Adv. Funct. Mater. 2022, 32, 2204291.
Teng, H.; Zheng, Y. M.; Cao, H.; Huang, Q.; Xiao, J. B.; Chen, L. Enhancement of bioavailability and bioactivity of diet-derived flavonoids by application of nanotechnology: A review. Crit. Rev. Food Sci. Nutr. 2023, 63, 378–393.
Zhou, D.; Bai, Z. S.; Guo, T. T.; Li, J. Y.; Li, Y. W.; Hou, Y.; Chen, G.; Li, N. Dietary flavonoids and human top-ranked diseases: The perspective of in vivo bioactivity and bioavailability. Trends Food Sci. Technol. 2022, 120, 374–386.
Cao, H.; Yang, L.; Tian, R.; Wu, H. X.; Gu, Z. P.; Li, Y. W. Versatile polyphenolic platforms in regulating cell biology. Chem. Soc. Rev. 2022, 51, 4175–4198.
Gao, X. Z.; Xu, Z. J.; Liu, G. T.; Wu, J. Polyphenols as a versatile component in tissue engineering. Acta Biomater. 2021, 119, 57–74.
Xu, Z. J.; Liu, G. T.; Zheng, L.; Wu, J. A polyphenol-modified chitosan hybrid hydrogel with enhanced antimicrobial and antioxidant activities for rapid healing of diabetic wounds. Nano Res. 2023, 16, 905–916.
Wang, Y. N.; Zhang, J. W.; Zhao, Y.; Pu, M. J.; Song, X. Y.; Yu, L. M.; Yan, X. F.; Wu, J.; He, Z. Y. Innovations and challenges of polyphenol-based smart drug delivery systems. Nano Res. 2022, 15, 8156–8184.
Yuan, D.; Guo, Y. J.; Pu, F. Y.; Yang, C.; Xiao, X. C.; Du, H. Z.; He, J. H.; Lu, S. Opportunities and challenges in enhancing the bioavailability and bioactivity of dietary flavonoids: A novel delivery system perspective. Food Chem. 2024, 430, 137115.
Chu, B. B.; Wu, S. C.; Yang, Y. M.; Song, B.; Wang, H. Y.; He, Y. Multifunctional flavonoid-silica nanohydrogel enables simultaneous inhibition of tumor recurrence and bacterial infection in post-surgical treatment. Small 2022, 18, 2104578.
Gui, S. Y.; Tang, W. W.; Huang, Z. H.; Wang, X. C.; Gui, S. Y.; Gao, X.; Xiao, D. C.; Tao, L. M.; Jiang, Z. X.; Wang, X. W. Ultrasmall coordination polymer nanodots Fe-quer nanozymes for preventing and delaying the development and progression of diabetic retinopathy. Adv. Funct. Mater. 2023, 33, 2300261.
Liu, Z. Q.; Chen, X. Y.; Ma, W. J.; Gao, Y.; Yao, Y. X.; Li, J. J.; Zhang, T. X.; Qin, X.; Ge, Y. C.; Jiang, Y. Y. et al. Suppression of lipopolysaccharide-induced sepsis by tetrahedral framework nucleic acid loaded with quercetin. Adv. Funct. Mater. 2022, 32, 2204587.
Han, Z. H.; Gao, X.; Wang, Y. J.; Cheng, S. N.; Zhong, X. Y.; Xu, Y.; Zhou, X. Z.; Zhang, Z. L.; Liu, Z.; Cheng, L. Ultrasmall iron-quercetin metal natural product nanocomplex with antioxidant and macrophage regulation in rheumatoid arthritis. Acta Pharm. Sin. B 2023, 13, 1726–1739.
Wang, Z. J.; Lu, J. H.; Yuan, Z. H.; Pi, W. M.; Huang, X. M.; Lin, X. Y.; Zhang, Y. Z.; Lei, H. M.; Wang, P. L. Natural carrier-free binary small molecule self-assembled hydrogel synergize antibacterial effects and promote wound healing by inhibiting virulence factors and alleviating the inflammatory response. Small 2023, 19, 2205528.
Khan, H.; Ullah, H.; Martorell, M.; Valdes, S. E.; Belwal, T.; Tejada, S.; Sureda, A.; Kamal, M. A. Flavonoids nanoparticles in cancer: Treatment, prevention and clinical prospects. Semin. Cancer Biol. 2021, 69, 200–211.
Zhu, F.; Zhong, J.; Hu, J. F.; Yang, P.; Zhang, J. H.; Zhang, M. H.; Li, Y. W.; Gu, Z. P. Carrier-free deferoxamine nanoparticles against iron overload in brain. CCS Chem. 2023, 5, 257–270.
Xu, Y. T.; Hu, J. F.; Hu, J. J.; Cheng, Y. Y.; Chen, X. C.; Gu, Z. P.; Li, Y. W. Bioinspired polydopamine hydrogels: Strategies and applications. Prog. Polym. Sci. 2023, 146, 101740.
Ibrahim, M.; Ramadan, E.; Elsadek, N. E.; Emam, S. E.; Shimizu, T.; Ando, H.; Ishima, Y.; Elgarhy, O. H.; Sarhan, H. A.; Hussein, A. K. et al. Polyethylene glycol (PEG): The nature, immunogenicity, and role in the hypersensitivity of PEGylated products. J. Control. Release 2022, 351, 215–230.
Suk, J. S.; Xu, Q. G.; Kim, N.; Hanes, J.; Ensign, L. M. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv. Drug Deliv. Rev. 2016, 99, 28–51.
D'souza, A. A.; Shegokar, R. Polyethylene glycol (PEG): A versatile polymer for pharmaceutical applications. Expert Opin. Drug Deliv. 2016, 13, 1257–1275.
Li, K. C.; Wang, W. J.; Gao, J. M. Fast and stable N-terminal cysteine modification through thiazolidino boronate mediated acyl transfer. Angew. Chem., Int. Ed. 2020, 59, 14246–14250.
Gehringer, M.; Laufer, S. A. Emerging and Re-emerging warheads for targeted covalent inhibitors: Applications in medicinal chemistry and chemical biology. J. Med. Chem. 2019, 62, 5673–5724.
Lu, J. J.; Gao, X.; Wang, S. Y.; He, Y.; Ma, X. W.; Zhang, T. B.; Liu, X. L. Advanced strategies to evade the mononuclear phagocyte system clearance of nanomaterials. Exploration 2023, 3, 20220045.
Du, Y. J.; Huo, Y.; Yang, Q.; Han, Z. H.; Hou, L. Q.; Cui, B. X.; Fan, K.; Qiu, Y. K.; Chen, Z.; Huang, W. P. et al. Ultrasmall iron-gallic acid coordination polymer nanodots with antioxidative neuroprotection for PET/MR imaging-guided ischemia stroke therapy. Exploration 2023, 3, 20220041.
Wang, L. L.; He, S. S.; Liu, R.; Xue, Y.; Quan, Y.; Shi, R. Y.; Yang, X. Y.; Lin, Q.; Sun, X.; Zhang, Z. R. et al. A pH/ROS dual-responsive system for effective chemoimmunotherapy against melanoma via remodeling tumor immune microenvironment. Acta Pharm. Sin. B 2024, 14, 2263–2280.
Zeng, Z.; Ouyang, J.; Sun, L. H.; Zeng, F.; Wu, S. Z. A biomarker-responsive nanosystem with colon-targeted delivery for ulcerative colitis's detection and treatment with optoacoustic/NIR-II fluorescence imaging. Adv. Healthcare Mater. 2022, 11, 2201544.
Yang, L.; Li, L.; Li, H. T.; Wang, T. Y.; Ren, X. C.; Cheng, Y. Y.; Li, Y. W.; Huang, Q. Layer-by-layer assembled smart antibacterial coatings via mussel-inspired polymerization and dynamic covalent chemistry. Adv. Healthcare Mater. 2022, 11, 2200112.
Yang, L.; Wang, C. P.; Li, L.; Zhu, F.; Ren, X. C.; Huang, Q.; Cheng, Y. Y.; Li, Y. W. Bioinspired integration of naturally occurring molecules towards universal and smart antibacterial coatings. Adv. Funct. Mater. 2022, 32, 2108749.
Hu, X. H.; Li, Z.; Yang, Z.; Zhu, F.; Zhao, W. F.; Duan, G. G.; Li, Y. W. Fabrication of functional polycatechol nanoparticles. ACS Macro Lett. 2022, 11, 251–256.
Zhang, H. J.; Xiao, Y.; Wang, T. Y.; Song, Y. X.; Zhang, R.; Duan, G. G.; Gu, Z. P.; Li, Y. W. Solvent and low temperature resistant natural polyphenolic adhesives. Polymer 2024, 299, 126929.
Bandyopadhyay, A.; Gao, J. M. Iminoboronate-based peptide cyclization that responds to pH, oxidation, and small molecule modulators. J. Am. Chem. Soc. 2016, 138, 2098–2101.
Bandyopadhyay, A.; McCarthy, K. A.; Kelly, M. A.; Gao, J. M. Targeting bacteria via iminoboronate chemistry of amine-presenting lipids. Nat. Commun. 2015, 6, 6561.
Yuan, T. Y.; Wang, T. Y.; Zhang, J. H.; Liu, P. Y.; Xu, J. Y.; Gu, Z. P.; Xu, J. G.; Li, Y. W. Robust and multifunctional nanoparticles assembled from natural polyphenols and metformin for efficient spinal cord regeneration. ACS Nano 2023, 17, 18562–18575.
Zuo, Y. M.; Ye, J. J.; Cai, W. X.; Guo, B. J.; Chen, X. F.; Lin, L. M.; Jin, S.; Zheng, H. Y.; Fang, A.; Qian, X. R. et al. Controlled delivery of a neurotransmitter-agonist conjugate for functional recovery after severe spinal cord injury. Nat. Nanotechnol. 2023, 18, 1230–1240.
Wang, H.; Lin, F.; Wu, Y.; Guo, W.; Chen, X. S.; Xiao, C. S.; Chen, M. W. Carrier-free nanodrug based on Co-assembly of methylprednisolone dimer and rutin for combined treatment of spinal cord injury. ACS Nano 2023, 17, 12176–12187.
Yuan, T. Y.; Wang, T. Y.; Zhang, J. H.; Shi, S.; Gu, Z. P.; Li, Y. W.; Xu, J. G. Procyanidins boost the neuroprotective effect of minocycline for intracerebral haemorrhage. Adv. Funct. Mater. 2023, 33, 2303379.
Xiang, X. H.; Fu, Y. N.; Zhao, K.; Miao, R. C.; Zhang, X.; Ma, X. H.; Liu, C.; Zhang, N.; Qu, K. Cellular senescence in hepatocellular carcinoma induced by a long non-coding RNA-encoded peptide PINT87aa by blocking FOXM1-mediated PHB2. Theranostics 2021, 11, 4929–4944.
Sun, W.; Chen, Y. X.; Wang, L.; Wang, Z.; Liu, S. W.; Zhang, M. Z.; Liu, Y.; Li, Q. S.; Zhang, H. Gram-scale preparation of quercetin supramolecular nanoribbons for intestinal inflammatory diseases by oral administration. Biomaterials 2023, 295, 122039.
Yang, S. Y.; Hu, Y.; Zhao, R.; Zhou, Y. N.; Zhuang, Y.; Zhu, Y.; Ge, X. L.; Lu, T. W.; Lin, K. L.; Xu, Y. J. Quercetin-loaded mesoporous nano-delivery system remodels osteoimmune microenvironment to regenerate alveolar bone in periodontitis via the miR-21a-5p/PDCD4/NF-κB pathway. J. Nanobiotechnol. 2024, 22, 94.
Jin, S.; Gao, J.; Yang, R. L.; Yuan, C.; Wang, R. L.; Zou, Q.; Zuo, Y.; Zhu, M. F.; Li, Y. B.; Man, Y. et al. A baicalin-loaded coaxial nanofiber scaffold regulated inflammation and osteoclast differentiation for vascularized bone regeneration. Bioact. Mater. 2022, 8, 559–572.
Yang, H. B.; Yu, Z. Y.; Ji, S. S.; Yan, J.; Kong, Y.; Huo, Q.; Zhang, Z. J.; Niu, Y. M.; Liu, Y. Regulation of synovial macrophages polarization by mimicking efferocytosis for therapy of osteoarthritis. Adv. Funct. Mater. 2022, 32, 2207637.
Wang, Y.; Li, C. Y.; Wan, Y.; Qi, M. L.; Chen, Q. H.; Sun, Y.; Sun, X. L.; Fang, J.; Fu, L.; Xu, L. et al. Quercetin-loaded ceria nanocomposite potentiate dual-directional immunoregulation via macrophage polarization against periodontal inflammation. Small 2021, 17, 2101505.
Wang, Z. J.; You, W. J.; Wang, W.; Tian, W. Q.; Chen, F. J.; Xiao, Y.; Chen, Y.; Wang, X. H. Dihydromyricetin-incorporated multilayer nanofibers accelerate chronic wound healing by remodeling the harsh wound microenvironment. Adv. Fiber Mater. 2022, 4, 1556–1571.
Fan, Q. Q.; Yang, Z.; Li, Y. H.; Cheng, Y. Y.; Li, Y. W. Polycatechol mediated small interfering RNA delivery for the treatment of ulcerative colitis. Adv. Funct. Mater. 2021, 31, 2101646.
Sun, H. X.; Zhan, M. S.; Karpus, A.; Zou, Y.; Li, J.; Mignani, S.; Majoral, J. P.; Shi, X. Y.; Shen, M. W. Bioactive phosphorus dendrimers as a universal protein delivery system for enhanced anti-inflammation therapy. ACS Nano 2024, 18, 2195–2209.
Li, Y.; Wang, Y. P.; Ding, Y. Y.; Fan, X.; Ye, L. S.; Pan, Q. Q.; Zhang, B. W.; Li, P.; Luo, K.; Hu, B. et al. A double network composite hydrogel with self-regulating Cu2+/luteolin release and mechanical modulation for enhanced wound healing. ACS Nano 2024, 18, 17251–17266.
Fatima, M.; Almalki, W. H.; Khan, T.; Sahebkar, A.; Kesharwani, P. Harnessing the power of stimuli-responsive nanoparticles as an effective therapeutic drug delivery system. Adv. Mater. 2024, 36, 2312939.
Yuan, T. Y.; Wang, T. Y.; Zhang, J. H.; Ye, F.; Gu, Z. P.; Li, Y. W.; Xu, J. G. Functional polyphenol-based nanoparticles boosted the neuroprotective effect of riluzole for acute spinal cord injury. Biomacromolecules 2024, 25, 2607–2620.
Hu, X.; Xu, W.; Ren, Y. L.; Wang, Z. J.; He, X. L.; Huang, R. Z.; Ma, B.; Zhao, J. W.; Zhu, R. R.; Cheng, L. M. Spinal cord injury: Molecular mechanisms and therapeutic interventions. Sig. Transduct. Target. Ther. 2023, 8, 245.
Ortega, M. A.; Fraile-Martinez, O.; García-Montero, C.; Haro, S.; Álvarez-Mon, M. Á.; De Leon-Oliva, D.; Gomez-Lahoz, A. M.; Monserrat, J.; Atienza-Pérez, M.; Díaz, D. et al. A comprehensive look at the psychoneuroimmunoendocrinology of spinal cord injury and its progression: Mechanisms and clinical opportunities. Military Med. Res. 2023, 10, 26.
Shen, K.; Li, X. W.; Huang, G. N.; Yuan, Z. W.; Xie, B.; Chen, T. F.; He, L. Z. High rapamycin-loaded hollow mesoporous Prussian blue nanozyme targets lesion area of spinal cord injury to recover locomotor function. Biomaterials 2023, 303, 122358.
Sun, Y. Y.; Zhu, H. J.; Zhao, R. Y.; Zhou, S. Y.; Wang, M. Q.; Yang, Y.; Guo, Z. N. Remote ischemic conditioning attenuates oxidative stress and inflammation via the Nrf2/HO-1 pathway in MCAO mice. Redox Biol. 2023, 66, 102852.
Wang, X. H.; Zhang, J. H.; Yang, L.; Wang, T. Y.; Duan, G. G.; Gu, Z. P.; Li, Y. W. Eumelanin-like poly(levodopa) nanoscavengers for inflammation disease therapy. Biomacromolecules 2024, 25, 2563–2573.
Xu, T.; Gao, P.; Huang, Y. F.; Wu, M. Y.; Yi, J.; Zhou, Z.; Zhao, X.; Jiang, T.; Liu, H.; Qin, T. et al. Git1-PGK1 interaction achieves self-protection against spinal cord ischemia-reperfusion injury by modulating Keap1/Nrf2 signaling. Redox Biol. 2023, 62, 102682.
Guo, X. D.; Kang, J. H.; Wang, Z. H.; Wang, Y. D.; Liu, M. Q.; Zhu, D. X.; Yang, F. G.; Kang, X. W. Nrf2 Signaling in the oxidative stress response after spinal cord injury. Neuroscience 2022, 498, 311–324.
Zhao, W. Y.; Gasterich, N.; Clarner, T.; Voelz, C.; Behrens, V.; Beyer, C.; Fragoulis, A.; Zendedel, A. Astrocytic Nrf2 expression protects spinal cord from oxidative stress following spinal cord injury in a male mouse model. J. Neuroinflammation 2022, 19, 134.
Lu, Y.; Sun, Y. Z.; Liu, Z. H.; Lu, Y. M.; Zhu, X.; Lan, B. X.; Mi, Z. Y.; Dang, L.; Li, N.; Zhan, W. L. et al. Activation of NRF2 ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease. Sci. Transl. Med. 2020, 12, eaba3613.
Chen, Y.; Luo, R. H.; Li, J.; Wang, S. F.; Ding, J. S.; Zhao, K.; Lu, B.; Zhou, W. H. Intrinsic radical species scavenging activities of tea polyphenols nanoparticles block pyroptosis in endotoxin-induced sepsis. ACS Nano 2022, 16, 2429–2441.
Liu, Y. X.; Lin, F.; Wu, C.; Liu, W. G.; Wang, H.; Xiao, C. S.; Chen, X. S. In situ reaction-generated aldehyde-scavenging polypeptides-curcumin conjugate nanoassemblies for combined treatment of spinal cord injury. ACS Nano 2024, 18, 7346–7362.
Zheng, J. D.; Chen, T. J.; Wang, K.; Peng, C.; Zhao, M. H.; Xie, Q. L.; Li, B.; Lin, H. S.; Zhao, Z.; Ji, Z. S. et al. Engineered multifunctional zinc-organic framework-based aggregation-induced emission nanozyme for accelerating spinal cord injury recovery. ACS Nano 2024, 18, 2355–2369.
You, Y. L.; Jiang, J. J.; Zheng, G.; Chen, Z. X.; Zhu, Y. X.; Ma, H. S.; Lin, H.; Guo, X.; Shi, J. L. In situ piezoelectric-catalytic anti-inflammation promotes the rehabilitation of acute spinal cord injury in synergy. Adv. Mater. 2024, 36, 2311429.
Jiang, C. X.; Qiu, W. W.; Yang, Y. Y.; Huang, H.; Dai, Z. M.; Yang, A. F.; Tang, T.; Zhao, X. F.; Qiu, M. S. ADAMTS4 enhances oligodendrocyte differentiation and remyelination by cleaving NG2 proteoglycan and attenuating PDGFRα signaling. J. Neurosci. 2023, 43, 4405–4417.
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