Abstract
Myocardial ischemia reperfusion (IR) injury is closely related to the overwhelming inflammation in the myocardium. Herein, cardiomyocyte-targeted nanotherapeutics were developed for the reactive oxygen species (ROS)-ultrasensitive co-delivery of dexamethasone (Dex) and RAGE small interfering RNA (siRAGE) to attenuate myocardial inflammation. PPTP, a ROS-degradable polycation based on PGE2-modified, PEGylated, ditellurium-crosslinked polyethylenimine (PEI) was developed to surface-decorate the Dex-encapsulated mesoporous silica nanoparticles (MSNs), which simultaneously condensed siRAGE and gated the MSNs to prevent the Dex pre-leakage. Upon intravenous injection to IR-injured rats, the nanotherapeutics could be efficiently transported into the inflamed cardiomyocytes via PGE2-assisted recognition of over-expressed E-series of prostaglandin (EP) receptors on the cell membranes. Intracellularly, the over-produced ROS degraded PPTP into small segments, promoting the release of siRAGE and Dex to mediate effective RAGE silencing (72%) and cooperative antiinflammatory effect. As a consequence, the nanotherapeutics notably suppressed the myocardial fibrosis and apoptosis, ultimately recovering the systolic function. Therefore, the current nanotherapeutics represent an effective example for the co-delivery and on-demand release of nucleic acid and chemodrug payloads, and might find promising utilities toward the synergistic management of myocardial inflammation.
Article PDF
Similar content being viewed by others
References
Li, Y.; Chen, X.; Jin, R. H.; Chen, L.; Dang, M.; Cao, H.; Dong, Y.; Cai, B. L.; Bai, G.; Gooding, J. et al. Injectable hydrogel with MSNs/microRNA-21-5p delivery enables both immunomodification and enhanced angiogenesis for myocardial infarction therapy in pigs. Sci. Adv. 2021, 7, eabd6740.
Huang, K.; Ozpinar, E. W.; Su, T.; Tang, J. N.; Shen, D. L.; Qiao, L.; Hu, S. Q.; Li, Z. H.; Liang, H. X.; Mathews, K. et al. An off-the-shelf artificial cardiac patch improves cardiac repair after myocardial infarction in rats and pigs. Sci. Transl. Med. 2020, 12, eaat9683.
Zhu, D. S.; Li, Z. H.; Huang, K.; Caranasos, T. G.; Rossi, J. S.; Cheng, K. Minimally invasive delivery of therapeutic agents by hydrogel injection into the pericardial cavity for cardiac repair. Nat. Commun. 2021, 12, 1412.
Li, Z. H.; Hu, S. Q.; Huang, K.; Su, T.; Cores, J.; Cheng, K. Targeted anti-IL-1β platelet microparticles for cardiac detoxing and repair. Sci. Adv. 2020, 6, eaay0589.
Li, Y.; Chen, X. G.; Li, P.; Xiao, Q. X.; Kong, X. Q. CD47 antibody suppresses isoproterenol-induced cardiac hypertrophy through activation of autophagy. Am. J. Transl. Res. 2020, 12, 5908–5923.
Li, Z. H.; Zhu, D. S.; Hui, Q.; Bi, J. N.; Yu, B. J.; Huang, Z.; Hu, S. Q.; Wang, Z. Z.; Caranasos, T.; Rossi, J. et al. Injection of ROS-responsive hydrogel loaded with basic fibroblast growth factor into the pericardial cavity for heart repair. Adv. Funct. Mater. 2021, 31, 2004377.
Hausenloy, D. J.; Yellon, D. M. Ischaemic conditioning and reperfusion injury. Nat. Rev. Cardiol. 2016, 13, 193–209.
Liu, M. R.; Lutz, H.; Zhu, D. S.; Huang, K.; Li, Z. H.; Dinh, P. U. C.; Gao, J. Q.; Zhang, Y.; Cheng, K. Bispecific antibody inhalation therapy for redirecting stem cells from the lungs to repair heart injury. Adv. Sci. 2021, 8, 2002127.
Su, T.; Huang, K.; Ma, H.; Liang, H. X.; Dinh, P. U.; Chen, J.; Shen, D. L.; Allen, T. A.; Qiao, L.; Li, Z. H. et al. Platelet-inspired nanocells for targeted heart repair after ischemia/reperfusion injury. Adv. Funct. Mater. 2019, 29, 1803567.
Liu, C. Y.; Zhang, Y. H.; Li, R. B.; Zhou, L. Y.; An, T.; Zhang, R. C.; Zhai, M.; Huang, Y.; Yan, K. W.; Dong, Y. H. et al. LncRNA CAIF inhibits autophagy and attenuates myocardial infarction by blocking p53-mediated myocardin transcription. Nat. Commun. 2018, 9, 29.
Tang, Y. Q.; Zeng, Z. Y.; He, X.; Wang, T. T.; Ning, X. H.; Feng, X. L. siRNA crosslinked nanoparticles for the treatment of inflammation-induced liver injury. Adv. Sci. 2017, 4, 1600228.
Shen, W. W.; Wang, R. J.; Fan, Q. Q.; Gao, X.; Wang, H.; Shen, Y.; Li, Y. W.; Cheng, Y. Y. Natural polyphenol inspired polycatechols for efficient siRNA delivery. CCS Chem. 2020, 2, 146–157.
Wang, M.; Alberti, K.; Varone, A.; Pouli, D.; Georgakoudi, I.; Xu, Q. B. Enhanced intracellular siRNA delivery using bioreducible lipid-like nanoparticles. Adv. Healthc. Mater. 2014, 3, 1398–1403.
Yang, J. D.; Duan, S. Z.; Ye, H.; Ge, C. L; Piao, C. X.; Chen, Y. B.; Lee, M.; Yin, L. C. Pro-peptide-reinforced, mucus-penetrating pulmonary siRNA delivery mitigates cytokine storm in pneumonia. Adv. Funct. Mater. 2021, 31, 2008960.
Hou, M. Y.; Wu, X. J.; Zhao, Z. Y.; Deng, Q. R.; Chen, Y. B.; Yin, L. C. Endothelial cell-targeting, ROS-ultrasensitive drug/siRNA co-delivery nanocomplexes mitigate early-stage neutrophil recruitment for the anti-inflammatory treatment of myocardial ischemia reperfusion injury. Acta Biomater. 2022, 143, 344–355.
Cai, C. D.; Zhang, X. S.; Li, Y. G.; Liu, X. Z.; Wang, S.; Lu, M. K.; Yan, X.; Deng, L. F.; Liu, S.; Wang, F. et al. Self-healing hydrogel embodied with macrophage-regulation and responsive-genesilencing properties for synergistic prevention of peritendinous adhesion. Adv. Mater. 2022, 34, 2106564.
Shen, S. Y.; Zhang, L.; Li, M. R.; Feng, Z. Z.; Li, H. X.; Xu, X.; Lin, S. Q.; Li, P.; Zhang, C.; Xu, X. J. et al. Collaborative assembly-mediated siRNA delivery for relieving inflammation-induced insulin resistance. Nano Res. 2020, 13, 2958–2966.
Hong, J.; Ku, S. H.; Lee, M. S.; Jeong, J. H.; Mok, H.; Choi, D.; Kim, S. H. Cardiac RNAi therapy using RAGE siRNA/deoxycholic acid-modified polyethylenimine complexes for myocardial infarction. Biomaterials 2014, 35, 7562–7573.
Liang, Q. J.; Li, F. F.; Li, Y. J.; Liu, Y.; Lan, M.; Wu, S. H.; Wu, X. J.; Ji, Y.; Zhang, R. J.; Yin, L. C. Self-assisted membranepenetrating helical polypeptides mediate anti-inflammatory RNAi against myocardial ischemic reperfusion (IR) injury. Biomater. Sci. 2019, 7, 3717–3728.
Piao, C. X.; Zhuang, C. Y.; Choi, M.; Ha, J.; Lee, M. A RAGE-antagonist peptide potentiates polymeric micelle-mediated intracellular delivery of plasmid DNA for acute lung injury gene therapy. Nanoscale 2020, 12, 13606–13617.
Dhumal, D.; Lan, W. J.; Ding, L.; Jiang, Y. F.; Lyu, Z.; Laurini, E.; Marson, D.; Tintaru, A.; Dusetti, N.; Giorgio, S. et al. An ionizable supramolecular dendrimer nanosystem for effective siRNA delivery with a favorable safety profile. Nano Res. 2021, 14, 2247–2254.
Shen, K.; Sun, G. D.; Chan, L.; He, L. Z.; Li, X. W.; Yang, S. X.; Wang, B. C.; Zhang, H.; Huang, J. R.; Chang, M. M. et al. Anti-inflammatory nanotherapeutics by targeting matrix metalloproteinases for immunotherapy of spinal cord injury. Small 2021, 17, 2102102.
Rinoldi, C.; Zargarian, S. S.; Nakielski, P.; Li, X. R.; Liguori, A.; Petronella, F.; Presutti, D.; Wang, Q. S.; Costantini, M.; De Sio, L. et al. Nanotechnology-assisted RNA delivery: From nucleic acid therapeutics to COVID-19 vaccines. Small Methods 2021, 5, 2100402.
Nie, J. J.; Qiao, B. K.; Duan, S.; Xu, C.; Chen, B. Y.; Hao, W. J.; Yu, B. R.; Li, Y. L.; Du, J.; Xu, F. J. Unlockable nanocomplexes with self-accelerating nucleic acid release for effective staged gene therapy of cardiovascular diseases. Adv. Mater. 2018, 30, 1801570.
Hao, K.; Guo, Z. P.; Lin, L.; Sun, P. J.; Li, Y. H.; Tian, H. Y.; Chen, X. S. Covalent organic framework nanoparticles for anti-tumor gene therapy. Sci. China Chem. 2021, 64, 1235–1241.
Xu, C. F.; Lu, Z. D.; Luo, Y. L.; Liu, Y.; Cao, Z. T.; Shen, S.; Li, H. J.; Liu, J.; Chen, K. G.; Chen, Z. Y. et al. Targeting of NLRP3 inflammasome with gene editing for the amelioration of inflammatory diseases. Nat. Commun. 2018, 9, 4092.
Weng, Y. H.; Xiao, H. H.; Zhang, J. C.; Liang, X. J.; Huang, Y. Y. RNAi therapeutic and its innovative biotechnological evolution. Biotechnol. Adv. 2019, 37, 801–825.
Ge, C. L.; Yang, J. D.; Duan, S. Z.; Liu, Y.; Meng, F. H.; Yin, L. C. Fluorinated α-helical polypeptides synchronize mucus permeation and cell penetration toward highly efficient pulmonary siRNA delivery against acute lung injury. Nano Lett. 2020, 20, 1738–1746.
Hu, B.; Li, B.; Li, K.; Liu, Y. Y.; Li, C. H.; Zheng, L. L.; Zhang, M. J.; Yang, T. R.; Guo, S.; Dong, X. Y. et al. Thermostable ionizable lipid-like nanoparticle (iLAND) for RNAi treatment of hyperlipidemia. Sci. Adv. 2022, 8, eabm1418.
Wang, C.; Liu, Q.; Zhang, Z. Z.; Wang, Y.; Zheng, Y. D.; Hao, J. L.; Zhao, X. Z.; Liu, Y.; Shi, L. Q. Tumor targeted delivery of siRNA by a nano-scale quaternary polyplex for cancer treatment. Chem. Eng. J. 2021, 425, 130590.
Ye, L.; Liu, H. M.; Fei, X.; Ma, D.; He, X. Z.; Tang, Q. Y.; Zhao, X.; Zou, H. B.; Chen, X. J.; Kong, X. M. et al. Enhanced endosomal escape of dendrigraft poly-L-lysine polymers for the efficient gene therapy of breast cancer. Nano Res. 2022, 15, 1135–1144.
Liu, Y.; Yin, L. C. α-Amino acid N-carboxyanhydride (NCA)-derived synthetic polypeptides for nucleic acids delivery. Adv. Drug Deliv. Rev 2021, 171, 139–163.
Liu, X.; Zhao, Z. Y.; Wu, F.; Chen, Y. B.; Yin, L. C. Tailoring hyperbranched poly(β-amino ester) as a robust and universal platform for cytosolic protein delivery. Adv. Mater. 2022, 34, 2108116.
Wen, L. J.; Peng, Y.; Wang, K.; Huang, Z. H.; He, S. Y.; Xiong, R. W.; Wu, L. P.; Zhang, F. T.; Hu, F. Q. Regulation of pathological BBB restoration via nanostructured ROS-responsive glycolipid-like copolymer entrapping siVEGF for glioblastoma targeted therapeutics. Nano Res. 2022, 15, 1455–1465.
Zheng, M.; Liu, Y. Y.; Wang, Y. B.; Zhang, D. Y.; Zou, Y.; Ruan, W. M.; Yin, J. L.; Tao, W.; Park, J. B.; Shi, B. Y. ROS-responsive polymeric siRNA nanomedicine stabilized by triple interactions for the robust glioblastoma combinational RNAi therapy. Adv. Mater. 2019, 31, 1903277.
Wang, J. X.; He, X. Y.; Shen, S.; Cao, Z. Y.; Yang, X. Z. ROSsensitive cross-linked polyethylenimine for red-light-activated siRNA therapy. ACS Appl. Mater. Interfaces 2019, 11, 1855–1863.
Zhang, M. J.; Weng, Y. H.; Cao, Z. Y.; Guo, S.; Hu, B.; Lu, M.; Guo, W. S.; Yang, T. R.; Li, C. H.; Yang, X. Z. et al. ROS-activatable siRNA-engineered polyplex for NIR-triggered synergistic cancer treatment. ACS Appl. Mater. Interfaces 2020, 12, 32289–32300.
Ye, H.; Zhou, Y.; Liu, X.; Chen, Y. B.; Duan, S. Z.; Zhu, R. Y.; Liu, Y.; Yin, L. C. Recent advances on reactive oxygen species-responsive delivery and diagnosis system. Biomacromolecules 2019, 20, 2441–2463.
Li, F.; Li, T. Y.; Cao, W.; Wang, L.; Xu, H. P. Near-infrared light stimuli-responsive synergistic therapy nanoplatforms based on the coordination of tellurium-containing block polymer and cisplatin for cancer treatment. Biomaterials 2017, 133, 208–218.
Zhou, W. Q.; Wang, L.; Li, F.; Zhang, W. N.; Huang, W.; Huo, F. W.; Xu, H. P. Selenium-containing polymer@metal-organic frameworks nanocomposites as an efficient multiresponsive drug delivery system. Adv. Funct. Mater. 2017, 27, 1605465.
Ji, S. B.; Cao, W.; Yu, Y.; Xu, H. P. Dynamic diselenide bonds: Exchange reaction induced by visible light without catalysis. Angew. Chem., Int. Ed. 2014, 53, 6781–6785.
Wang, H.; Zhang, S.; Lv, J.; Cheng, Y. Y. Design of polymers for siRNA delivery: Recent progress and challenges. View 2021, 2, 20200026.
Wen, Y. T.; Bai, H. Z.; Zhu, J. L.; Song, X.; Tang, G. P.; Li, J. A supramolecular platform for controlling and optimizing molecular architectures of siRNA targeted delivery vehicles. Sci. Adv. 2020, 6, eabc2148.
Zhuang, J.; Gong, H.; Zhou, J. R.; Zhang, Q. Z.; Gao, W. W.; Fang, R. H.; Zhang, L. F. Targeted gene silencing in vivo by platelet membrane-coated metal-organic framework nanoparticles. Sci. Adv. 2020, 6, eaaz6108.
Yan, J.; Liu, X.; Wu, F.; Ge, C. L.; Ye, H.; Chen, X. Y.; Wei, Y. S.; Zhou, R. X.; Duan, S. Z.; Zhu, R. Y. et al. Platelet pharmacytes for the hierarchical amplification of antitumor immunity in response to self-generated immune signals. Adv. Mater. 2022, 34, 2109517.
Bellis, A.; Mauro, C.; Barbato, E.; Di Gioia, G.; Sorriento, D.; Trimarco, B.; Morisco, C. The rationale of neprilysin inhibition in prevention of myocardial ischemia-reperfusion injury during ST-elevation myocardial infarction. Cells 2020, 9, 2134.
Hou, M. Y.; Wei, Y. S.; Zhao, Z. Y.; Han, W. Q.; Zhou, R. X.; Zhou, Y.; Zheng, Y. R.; Yin, L. C. Immuno-engineered nanodecoys for the multi-target anti-inflammatory treatment of autoimmune diseases. Adv. Mater. 2022, 34, 2108817.
Sager, H. B.; Dutta, P.; Dahlman, J. E.; Hulsmans, M.; Courties, G.; Sun, Y.; Heidt, T.; Vinegoni, C.; Borodovsky, A.; Fitzgerald, K. et al. RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction. Sci. Transl. Med. 2016, 8, 342ra80.
Wang, Y.; Hou, M. Y.; Duan, S. Z.; Zhao, Z. Y.; Wu, X. J.; Chen, Y. B.; Yin, L. C. Macrophage-targeting gene silencing orchestrates myocardial microenvironment remodeling toward the anti-inflammatory treatment of ischemia-reperfusion (IR) injury. Bioact. Mater. 2022, 17, 320–333.
Yin, N.; Tan, X. Y.; Liu, H. B.; He, F. M.; Ding, N.; Gou, J. X.; Yin, T.; He, H. B.; Zhang, Y.; Tang, X. A novel indomethacin/methotrexate/MMP-9 siRNA in situ hydrogel with dual effects of anti-inflammatory activity and reversal of cartilage disruption for the synergistic treatment of rheumatoid arthritis. Nanoscale 2020, 12, 8546–8562.
Wang, Q.; Jiang, H.; Li, Y.; Chen, W. F.; Li, H. M.; Peng, K.; Zhang, Z. R.; Sun, X. Targeting NF-kB signaling with polymeric hybrid micelles that co-deliver siRNA and dexamethasone for arthritis therapy. Biomaterials 2017, 122, 10–22.
Jiang, K. Y.; Weaver, J. D.; Li, Y. J. Y.; Chen, X. J.; Liang, J. P.; Stabler, C. L. Local release of dexamethasone from macroporous scaffolds accelerates islet transplant engraftment by promotion of anti-inflammatory M2 macrophages. Biomaterials 2017, 114, 71–81.
Li, X. D.; Wei, Y. S.; Wu, Y. C.; Yin, L. C. Hypoxia-induced proprotein therapy assisted by a self-catalyzed nanozymogen. Angew. Chem., Int. Ed. 2020, 59, 22544–22553.
Sun, P. C.; Scharnweber, T.; Wadhwani, P.; Rabe, K. S.; Niemeyer, C. M. DNA-directed assembly of a cell-responsive biohybrid interface for cargo release. Small Methods 2021, 5, 2001049.
Dong, P.; Hu, J. L.; Yu, S. Y.; Zhou, Y. Z.; Shi, T. H.; Zhao, Y.; Wang, X. Y.; Liu, X. Q. A mitochondrial oxidative stress amplifier to overcome hypoxia resistance for enhanced photodynamic therapy. Small Methods 2021, 5, 2100581.
Gan, Q.; Zhu, J. Y.; Yuan, Y.; Liu, H. L.; Qian, J. C.; Li, Y. S.; Liu, C. S. A dual-delivery system of pH-responsive chitosan-functionalized mesoporous silica nanoparticles bearing BMP-2 and dexamethasone for enhanced bone regeneration. J. Mater. Chem. B 2015, 3, 2056–2066.
Acknowledgements
We appreciate the funding support from the National Natural Science Foundation of China (No. 52033006 and 51873142), Suzhou Science and Technology Development Project (No. SYS2019072), Collaborative Innovation Center of Suzhou Nano Science & Technology, the 111 project, Suzhou Key Laboratory of Nanotechnology and Biomedicine, and Joint International Research Laboratory of Carbon-Based Functional Materials and Devices.
Author information
Authors and Affiliations
Corresponding authors
Electronic Supplementary Material
Rights and permissions
About this article
Cite this article
Lan, M., Hou, M., Yan, J. et al. Cardiomyocyte-targeted anti-inflammatory nanotherapeutics against myocardial ischemia reperfusion (IR) injury. Nano Res. 15, 9125–9134 (2022). https://doi.org/10.1007/s12274-022-4553-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12274-022-4553-6