Rational design of siRNA-based delivery systems for effective treatment of brain diseases

Dailin Lu; Yonghang Sun; Yuxia Luan; Wenxiu He

doi:10.1016/j.pscia.2024.100041

Pharmaceutical Science Advances ›› 2024, Vol. 2 ›› Issue (1) : 100041 DOI: 10.1016/j.pscia.2024.100041

Review Article

research-article

Rational design of siRNA-based delivery systems for effective treatment of brain diseases

Author information +

History +

PDF (5367KB)

Abstract

Effective clinical methods are urgently required to treat brain diseases. Small interfering RNAs (siRNAs) are promising in the treatment of brain diseases because of their ability to target and specifically silence genes associated with disease progression. However, their effectiveness is hindered by physiological barriers such as enzymatic degradation, the blood-brain barrier, and the blood-brain tumor barrier, severely restricting them from reaching the desired target sites. The development of nanotechnology has made the effective delivery of siRNAs to the brain possible. This is accomplished by encapsulating siRNAs in cationic polymers, liposomes, or micelles to improve their stability and targeting efficiency. In this review, we first analyzed the limitations of siRNA delivery in brain diseases such as brain tumors, stroke, and neurodegenerative diseases. Next, we summarized how nanotechnology can offer a solution by enabling effective siRNA delivery to the brain and improving the intracellular transfection efficiency of siRNA. Finally, we discussed the challenges and future advances of siRNA-based delivery systems to facilitate their clinical translation. This review emphasizes the importance of overcoming physiological barriers associated with siRNA delivery and highlights recent advances in the rational design of siRNA-based delivery systems for the effective treatment of brain diseases.

Keywords

siRNA therapy / Brain diseases / Blood-brain barrier / Brain targeting / Delivery systems

Cite this article

Download citation ▾

Dailin Lu, Yonghang Sun, Yuxia Luan, Wenxiu He. Rational design of siRNA-based delivery systems for effective treatment of brain diseases. Pharmaceutical Science Advances, 2024, 2(1): 100041 DOI:10.1016/j.pscia.2024.100041

登录浏览全文

4963

注册一个新账户忘记密码

Availability of data and material

Not applicable.

Ethics approval

Not applicable.

Funding

This review was financially supported by the National Natural Science Foundation of China (No. 82204305) and the Young Scholar Program of Shandong University (YSPSDU, 2023WLJH131).

Declaration of competing interest

The authors declare no conflict of interest.

Acknowledgements

We are grateful for the assistance provided by our colleagues at the School of Pharmaceutical Sciences, Shandong University. Fig. 1 was created using the BioRender.com software.

References

Publishing order | Descend order by publishing year | Descend order by cited within

[1]	A.P. Patel, J.L. Fisher, E. Nichols, Global regional, and national burden of brain and other CNS cancer, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016, Lancet Neurol. 18 (4) (2019) 376-393. https://doi.org/10.1016/S1474-4422(18)30468-X.

[2]

S.L.G. James, D. Abate, K.H. Abate, S.M. Abay, Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017, Lancet 392 (10159) (2018) 1789-1858. https://doi.org/10.1016/S0140-6736(18)32279-7.

[3]	B.G. Harder, M.R. Blomquist, J. Wang, A.J. Kim, G.F. Woodworth, J.A. Winkles, J.C. Loftus, N.L. Tran, Developments in blood-brain barrier penetrance and drug repurposing for improved treatment of glioblastoma, Front. Oncol. 8 (2018) 462. https://doi.org/10.3389/fonc.2018.00462.

[4]	W. He, Z. Zhang, X. Sha, Nanoparticles-mediated emerging approaches for effective treatment of ischemic stroke, Biomaterials 277 (2021) 121111. https://doi.org/10.1016/j.biomaterials.2021.121111.

[5]

R. Howard, R. McShane, J. Lindesay, C. Ritchie, A. Baldwin, R. Barber, A. Burns, T. Dening, D. Findlay, C. Holmes, R. Jones, R. Jones, I. McKeith, A. Macharouthu, J. O’Brien, B. Sheehan, E. Juszczak, C. Katona, R. Hills, M. Knapp, C. Ballard, R.G. Brown, S. Banerjee, J. Adams, T. Johnson, P. Bentham, P.P. Phillips, Nursing home placement in the donepezil and memantine in moderate to severe Alzheimer’s disease (DOMINO-AD) trial: secondary and post-hoc analyses, Lancet Neurol. 14 (2015) 1171-1181. https://doi.org/10.1016/S1474-4422(15)00258-6.

[6]	G.M. Chalbatani, H. Dana, E. Gharagouzloo, S. Grijalvo, R. Eritja, C.D. Logsdon, F. Memari, S.R. Miri, M.R. Rad, V. Marmari, Small interfering RNAs (siRNAs) in cancer therapy: a nano-based approach, Int. J. Nanomed. 14 (2019) 3111-3128. https://doi.org/10.2147/IJN.S200253.

[7]	J.A. Kulkarni, D. Witzigmann, S. Chen, P.R. Cullis, R. van der Meel, Lipid nanoparticle technology for clinical translation of siRNA therapeutics, Acc. Chem. Res. 52 (2019) 2435-2444. https://doi.org/10.1021/acs.accounts.9b00368.

[8]	S. Yonezawa, H. Koide, T. Asai, Recent advances in siRNA delivery mediated by lipid-based nanoparticles, Adv. Drug Deliv. Rev. 154 (2020) 64-78. https://doi.org/10.1016/j.addr.2020.07.022.

[9]	R.W. Carthew, E.J. Sontheimer, Origins and mechanisms of miRNAs and siRNAs, Cell 136 (2009) 642-655. https://doi.org/10.1016/j.cell.2009.01.035.

[10]	H. Gao, Progress and perspectives on targeting nanoparticles for brain drug delivery, Acta Pharm. Sin. B 6 (2016) 268-286. https://doi.org/10.1016/j.apsb.2016.05.013.

[11]	M. Zheng, W. Tao, Y. Zou, O.C. Farokhzad, B. Shi, Nanotechnology-based strategies for siRNA brain delivery for disease therapy, Trends Biotechnol. 36 (2018) 562-575. https://doi.org/10.1016/j.tibtech.2018.01.006.

[12]	K. Paunovska, D. Loughrey, J.E. Dahlman, Drug delivery systems for RNA therapeutics, Nat. Rev. Genet. 23 (2022) 265-280. https://doi.org/10.1038/s41576-021-00439-4.

[13]	B. Caffery, J.S. Lee, A.A. Alexander-Bryant, Vectors for glioblastoma gene therapy: viral & non-viral delivery strategies, Nanomaterials 9 (2019). XXXX, https://doi.org/10.3390/nano9010105.

[14]	W. Chen, Y. Hu, D. Ju, Gene therapy for neurodegenerative disorders: advances, insights and prospects, Acta Pharm. Sin. B 10 (2020) 1347-1359. https://doi.org/10.1016/j.apsb.2020.01.015.

[15]	G. Kara, G.A. Calin, B. Ozpolat, RNAi-based therapeutics and tumor targeted delivery in cancer, Adv. Drug Deliv. Rev. 182 (2022) 114113. https://doi.org/10.1016/j.addr.2022.114113.

[16]	Y. Dong, D.J. Siegwart, D.G. Anderson, Strategies, design, and chemistry in siRNA delivery systems, Adv. Drug Deliv. Rev. 144 (2019) 133-147. https://doi.org/10.1016/j.addr.2019.05.004.

[17]

N.B. Charbe, N.D. Amnerkar, B. Ramesh, M.M. Tambuwala, H.A. Bakshi, A.A.A. Aljabali, S.C. Khadse, R. Satheeshkumar, S. Satija, M. Metha, D.K. Chellappan, G. Shrivastava, G. Gupta, P. Negi, K. Dua, F.C. Zacconi, Small interfering RNA for cancer treatment: overcoming hurdles in delivery, Acta Pharm. Sin. B 10 (2020) 2075-2109. https://doi.org/10.1016/j.apsb.2020.10.005.

[18]	M.D. Sweeney, Z. Zhao, A. Montagne, A.R. Nelson, B.V. Zlokovic,Blood-brain barrier: from physiology to disease and back, Physiol. Rev. 99 (2019) 21-78. https://doi.org/10.1152/physrev.00050.2017.

[19]	N.J. Abbott, L. Ronnback, E. Hansson, Astrocyte-endothelial interactions at the blood-brain barrier, Nat. Rev. Neurosci. 7 (2006) 41-53. https://doi.org/10.1038/nrn1824.

[20]	C.D. Arvanitis, G.B. Ferraro, R.K. Jain, The blood-brain barrier and blood-tumour barrier in brain tumours and metastases, Nat. Rev. Cancer 20 (2020) 26-41. https://doi.org/10.1038/s41568-019-0205-x.

[21]	L. Han, C. Jiang, Evolution of blood-brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies, Acta Pharm. Sin. B 11 (2021) 2306-2325. https://doi.org/10.1016/j.apsb.2020.11.023.

[22]	R. Pandit, L. Chen, J. Gotz, The blood-brain barrier: physiology and strategies for drug delivery, Adv. Drug Deliv. Rev. 165-166 (2020) 1-14. https://doi.org/10.1016/j.addr.2019.11.009.

[23]	A. Parodi, M. Rudzinska, A.A. Deviatkin, S.M. Soond, A.V. Baldin, A.A. Zamyatnin Jr, Established and emerging strategies for drug delivery across the blood-brain barrier in brain cancer, Pharmaceutics 11 (245) (2019). https://doi.org/10.3390/pharmaceutics11050245.

[24]	D.H. Upton, C. Ung, S.M. George, M. Tsoli, M. Kavallaris, D.S. Ziegler, Challenges and opportunities to penetrate the blood-brain barrier for brain cancer therapy, Theranostics 12 (2022) 4734-4752. https://doi.org/10.7150/thno.69682.

[25]	J.M. Lajoie, E.V. Shusta, Targeting receptor-mediated transport for delivery of biologics across the blood-brain barrier, Annu. Rev. Pharmacol. Toxicol. 55 (2015) 613-631. https://doi.org/10.1146/annurev-pharmtox-010814-124852.

[26]

Y. Guo, H. Lee, Z. Fang, A. Velalopoulou, J. Kim, M.B. Thomas, J. Liu, R.G. Abramowitz, Y. Kim, A.F. Coskun, D.P. Krummel, S. Sengupta, T.J. MacDonald, C. Arvanitis, Single-cell analysis reveals effective siRNA delivery in brain tumors with microbubble-enhanced ultrasound and cationic nanoparticles, Sci. Adv. 7 (2021) eabf7390. https://doi.org/10.1126/sciadv.abf7390.

[27]

F. Wang, H. Wu, A. Hu, L. Dong, X. Lin, M. Li, Y. Wang, W. Li, L. Chang, Y. Chang, H. Liu, Y. Shi, N. Li, Ultrasound combined with glial cell line-derived neurotrophic factor-loaded microbubbles for the targeted treatment of drug addiction, Front. Bioeng. Biotechnol. 10 (2022) 961728. https://doi.org/10.3389/fbioe.2022.961728.

[28]

E. Hart, Z. Ode, M.P.P. Derieppe, L. Groenink, M.W. Heymans, R. Otten, M.H. Lequin, G.O.R. Janssens, E.W. Hoving, D.G. van Vuurden, Blood-brain barrier permeability following conventional photon radiotherapy - a systematic review and meta-analysis of clinical and preclinical studies, Clin. Transl. Radiat. Oncol. 35 (2022) 44-55. https://doi.org/10.1016/j.ctro.2022.04.013.

[29]

T.A. Arsiwala, K.E. Blethen, C.P. Wolford, D.M. Panchal, S.A. Sprowls, R.A. Fladeland, B.N. Kielkowski, T.A. Pritt, P. Wang, O. Wilson, J.S. Carpenter, V. Finomore, A. Rezai, P.R. Lockman, Blood-tumor barrier opening by MRI-guided transcranial focused ultrasound in a preclinical breast cancer brain metastasis model improves efficacy of combinatorial chemotherapy, Front. Oncol. 13 (2023) 1104594. https://doi.org/10.3389/fonc.2023.1104594.

[30]	F. Moradi, N. Dashti, Targeting neuroinflammation by intranasal delivery of nanoparticles in neurological diseases: a comprehensive review, Naunyn- Schmiedeberg’s Arch. Pharmacol. 395 (2022) 133-148. https://doi.org/10.1007/s00210-021-02196-x.

[31]	L.A. Keller, O. Merkel, A. Popp, Intranasal drug delivery: opportunities and toxicologic challenges during drug development, Drug Deliv. Transl. Res. 12 (2022) 735-757. https://doi.org/10.1007/s13346-020-00891-5.

[32]	M. Agrawal, S. Saraf, S. Saraf, S.G. Antimisiaris, M.B. Chougule, S.A. Shoyele, A. Alexander, Nose-to-brain drug delivery: an update on clinical challenges and progress towards approval of anti-Alzheimer drugs, J. Contr. Release 281 (2018) 139-177. https://doi.org/10.1007/s13346-020-00891-5.

[33]	J.A. Barcia, J.M. Gallego, Intraventricular and intracerebral delivery of antiepileptic drugs in the kindling model, Neurotherapeutics 6 (2009) 337-343. https://doi.org/10.1016/j.nurt.2009.01.015.

[34]	S. Li, D. Jiang, E.B. Ehlerding, Z.T. Rosenkrans, J.W. Engle, Y. Wang, H. Liu, D. Ni, W. Cai, Intrathecal administration of nanoclusters for protecting neurons against oxidative stress in cerebral ischemia/reperfusion injury, ACS Nano 13 (2019) 13382-13389. https://doi.org/10.1021/acsnano.9b06780.

[35]

H. Peng, Y. Li, W. Ji, R. Zhao, Z. Lu, J. Shen, Y. Wu, J. Wang, Q. Hao, J. Wang, W. Wang, J. Yang, X. Zhang, Intranasal administration of self-oriented nanocarriers based on therapeutic exosomes for synergistic treatment of Parkinson’s disease, ACS Nano 16 (2022) 869-884. https://doi.org/10.1021/acsnano.1c08473.

[36]	P. Wesseling, D. Capper, WHO 2016 classification of gliomas, Neuropathol, Appl. Neurobiol. 44 (2018) 139-150. https://doi.org/10.1111/nan.12432.

[37]

D.N. Louis, A. Perry, P. Wesseling, D.J. Brat, I.A. Cree, D. Figarella-Branger, C. Hawkins, H.K. Ng, S.M. Pfister, G. Reifenberger, R. Soffietti, A. von Deimling, D.W. Ellison, The 2021 WHO classification of tumors of the central nervous system: a summary, Neuro Oncol. 23 (2021) 1231-1251. https://doi.org/10.1093/neuonc/noab106.

[38]	S. Xu, L. Tang, X. Li, F. Fan, Z. Liu, Immunotherapy for glioma: current management and future application, Cancer Lett. 476 (2020) 1-12. https://doi.org/10.1016/j.canlet.2020.02.002.

[39]

M. Weller, M. van den Bent, J.C. Tonn, R. Stupp, M. Preusser, E. Cohen-Jonathan- Moyal, R. Henriksson, E. Le Rhun, C. Balana, O. Chinot, M. Bendszus, J.C. Reijneveld, F. Dhermain, P. French, C. Marosi, C. Watts, I. Oberg, G. Pilkington, B.G. Baumert, M.J.B. Taphoorn, M. Hegi, M. Westphal, G. Reifenberger, R. Soffietti, W. Wick, G. European Association for Neuro- Oncology, European Association for Neuro-Oncology, (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas, Lancet Oncol. 18 (2017) e315-e329, https://doi.org/10.1016/S1470-2045(17)30194-8.

[40]	T. Komori, Grading of adult diffuse gliomas according to the 2021 WHO classification of tumors of the central nervous system, Lab. Invest. 102 (2022) 126-133. https://doi.org/10.1038/s41374-021-00667-6.

[41]	K. Messaoudi, A. Clavreul, F. Lagarce, Toward an effective strategy in glioblastoma treatment. Part I: resistance mechanisms and strategies to overcome resistance of glioblastoma to temozolomide, Drug Discov. Today 20 (2015) 899-905. https://doi.org/10.1016/j.drudis.2015.02.011.

[42]

E. Le Rhun, S. Taillibert, F. Zairi, N. Kotecki, P. Devos, A. Mailliez, V. Servent, L. Vanlemmens, P. Vennin, T. Boulanger, M.C. Baranzelli, C. Andre, G. Marliot, J.L. Cazin, F. Dubois, R. Assaker, J. Bonneterre, M.C. Chamberlain, A retrospective case series of 103 consecutive patients with leptomeningeal metastasis and breast cancer, J. Neuro Oncol. 113 (2013) 83-92. https://doi.org/10.1007/s11060-013-1092-8.

[43]	X.Q. Teng, J. Qu, G.H. Li, H.H. Zhuang, Q. Qu, Small interfering RNA for gliomas treatment: overcoming hurdles in delivery, Front. Cell Dev. Biol. 10 (2022) 824299. https://doi.org/10.3389/fcell.2022.824299.

[44]	N. Khatri, M. Rathi, D. Baradia, S. Trehan, A. Misra, In vivo delivery aspects of miRNA, shRNA and siRNA, Crit. Rev. Ther. Drug Carrier Syst. 29 (2012) 487-527. https://doi.org/10.1615/CritRevTherDrugCarrierSyst.v29.i6.20.

[45]

M. Van Woensel, N. Wauthoz, R. Rosiere, V. Mathieu, R. Kiss, F. Lefranc, B. Steelant, E. Dilissen, S.W. Van Gool, T. Mathivet, H. Gerhardt, K. Amighi, S. De Vleeschouwer, Development of siRNA-loaded chitosan nanoparticles targeting Galectin-1 for the treatment of glioblastoma multiforme via intranasal administration, J. Contr. Release 227 (2016) 71-81. https://doi.org/10.1016/j.jconrel.2016.02.032.

[46]

J.H. Azambuja, R.S. Schuh, L.R. Michels, N.E. Gelsleichter, L.R. Beckenkamp, I.C. Iser, G.S. Lenz, F.H. de Oliveira, G. Venturin, S. Greggio, J.C. daCosta, M.R. Wink, J. Sevigny, M.A. Stefani, A.M.O. Battastini, H.F. Teixeira, E. Braganhol, Nasal administration of cationic nanoemulsions as CD73-siRNA delivery system for glioblastoma treatment: a new therapeutical approach, Mol. Neurobiol. 57 (2020) 635-649. https://doi.org/10.1007/s12035-019-01730-6.

[47]

L. Wang, Y. Hao, H. Li, Y. Zhao, D. Meng, D. Li, J. Shi, H. Zhang, Z. Zhang, Y. Zhang, Co-delivery of doxorubicin and siRNA for glioma therapy by a brain targeting system: angiopep-2-modified poly(lactic-co-glycolic acid) nanoparticles, J. Drug Target. 23 (2015) 832-846. https://doi.org/10.3109/1061186X.2015.1025077.

[48]	L. Wei, X.Y. Guo, T. Yang, M.Z. Yu, D.W. Chen, J.C. Wang, Brain tumor-targeted therapy by systemic delivery of siRNA with transferrin receptor-mediated coreshell nanoparticles, Int. J. Pharm. 510 (2016) 394-405. https://doi.org/10.1016/j.ijpharm.2016.06.127.

[49]	Y. Yang, X. Zhang, S. Wu, R. Zhang, B. Zhou, X. Zhang, L. Tang, Y. Tian, K. Men, L. Yang, Enhanced nose-to-brain delivery of siRNA using hyaluronan-enveloped nanomicelles for glioma therapy, J. Contr. Release 342 (2022) 66-80. https://doi.org/10.1016/j.jconrel.2021.12.034.

[50]	Y. Zou, X. Sun, Y. Wang, C. Yan, Y. Liu, J. Li, D. Zhang, M. Zheng, R.S. Chung, B. Shi, Single siRNA nanocapsules for effective siRNA brain delivery and glioblastoma treatment, Adv. Mater. 32 (2020) e2000416. https://doi.org/10.1002/adma.202000416.

[51]	H. Shi, S. Sun, H. Xu, Z. Zhao, Z. Han, J. Jia, D. Wu, J. Lu, H. Liu, R. Yu, Combined delivery of temozolomide and siPLK1 using targeted nanoparticles to enhance temozolomide sensitivity in glioma, Int. J. Nanomed. 15 (2020) 3347-3362. https://doi.org/10.2147/IJN.S243878.

[52]	M. Zheng, Y. Liu, Y. Wang, D. Zhang, Y. Zou, W. Ruan, J. Yin, W. Tao, J.B. Park, B. Shi, ROS-responsive polymeric siRNA nanomedicine stabilized by triple interactions for the robust glioblastoma combinational RNAi therapy, Adv. Mater. 31 (2019) e1903277, https://doi.org/10.1002/adma.201903277.

[53]	X. Sun, Y. Chen, H. Zhao, G. Qiao, M. Liu, C. Zhang, D. Cui, L. Ma, Dual-modified cationic liposomes loaded with paclitaxel and survivin siRNA for targeted imaging and therapy of cancer stem cells in brain glioma, Drug Deliv. 25 (2018) 1718-1727. https://doi.org/10.1080/10717544.2018.1494225.

[54]	N.M. Anderson, M.C. Simon, The tumor microenvironment, Curr. Biol. 30 (2020) R921-R925. https://doi.org/10.1016/j.cub.2020.06.081.

[55]	M. Le Mercier, S. Fortin, V. Mathieu, R. Kiss, F. Lefranc, Galectins and gliomas, Brain Pathol. 20 (2010) 17-27. https://doi.org/10.1111/j.1750-3639.2009.00270.x.

[56]

N. Rubinstein, M. Alvarez, N.W. Zwirner, M.A. Toscano, J.M. Ilarregui, A. Bravo, J. Mordoh, L. Fainboim, O.L. Podhajcer, G.A. Rabinovich, Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection; A potential mechanism of tumor-immune privilege, Cancer Cell 5 (2004) 241-251. https://doi.org/10.1016/S1535-6108(04)00024-8.

[57]

J.H. Azambuja, N.E. Gelsleichter, L.R. Beckenkamp, I.C. Iser, M.C. Fernandes, F. Figueiro, A.M.O. Battastini, J.N. Scholl, F.H. de Oliveira, R.M. Spanevello, J. Sevigny, M.R. Wink, M.A. Stefani, H.F. Teixeira, E. Braganhol, CD 73 downregulation decreases in vitro and in vivo glioblastoma growth, Mol. Neurobiol. 56 (2019) 3260-3279. https://doi.org/10.1007/s12035-018-1240-4.

[58]	M.H. Kazemi, S. Raoofi Mohseni, M. Hojjat-Farsangi, E. Anvari, G. Ghalamfarsa, H. Mohammadi, F. Jadidi-Niaragh, Adenosine and adenosine receptors in the immunopathogenesis and treatment of cancer, J. Cell Physiol. 233 (2018) 2032-2057. https://doi.org/10.1002/jcp.25873.

[59]	F. Lopes-Coelho, F. Martins, S.A. Pereira, J. Serpa, Anti-angiogenic therapy: current challenges and future perspectives, Int. J. Mol. Sci. 22 (2021) 3765. https://doi.org/10.3390/ijms22073765.

[60]	K. Zarschler, K. Prapainop, E. Mahon, L. Rocks, M. Bramini, P.M. Kelly, H. Stephan, K.A. Dawson, Diagnostic nanoparticle targeting of the EGF-receptor in complex biological conditions using single-domain antibodies, Nanoscale 6 (2014) 6046-6056. https://doi.org/10.1039/C4NR00595C.

[61]

Y. Zhang, Y.F. Zhang, J. Bryant, A. Charles, R.J. Boado, W.M. Pardridge, Intravenous RNA interference gene therapy targeting the human epidermal growth factor receptor prolongs survival in intracranial brain cancer, Clin. Cancer Res. 10 (2004) 3667-3677. https://doi.org/10.1158/1078-0432.CCR-03-0740.

[62]	M. Demeule, A. Regina, C. Che, J. Poirier, T. Nguyen, R. Gabathuler, J.P. Castaigne, R. Beliveau, Identification and design of peptides as a new drug delivery system for the brain, J. Pharmacol. Exp. Therapeut. 324 (2008) 1064-1072. https://doi.org/10.1124/jpet.107.131318.

[63]

T. Kang, M. Jiang, D. Jiang, X. Feng, J. Yao, Q. Song, H. Chen, X. Gao, J. Chen, Enhancing glioblastoma-specific penetration by functionalization of nanoparticles with an iron-mimic peptide targeting transferrin/transferrin receptor complex, Mol. Pharm. 12 (2015) 2947-2961. https://doi.org/10.1021/acs.molpharmaceut.5b00222.

[64]	L. Han, J. Li, S. Huang, R. Huang, S. Liu, X. Hu, P. Yi, D. Shan, X. Wang, H. Lei, C. Jiang, Peptide-conjugated polyamidoamine dendrimer as a nanoscale tumortargeted T1 magnetic resonance imaging contrast agent, Biomaterials 32 (2011) 2989-2998. https://doi.org/10.1016/j.biomaterials.2011.01.005.

[65]	J. Fares, M.Y. Fares, H.H. Khachfe, H.A. Salhab, Y. Fares, Molecular principles of metastasis: a hallmark of cancer revisited, Signal Transduct. Targeted Ther. 28 (5) (2020). https://doi.org/10.1038/s41392-020-0134-x.

[66]

F. Higuchi, A.L. Fink, J. Kiyokawa, J.J. Miller, M.V.A. Koerner, D.P. Cahill, H. Wakimoto, PLK 1 inhibition targets myc-activated malignant glioma cells irrespective of mismatch repair deficiency-mediated acquired resistance to temozolomide, Mol. Cancer Therapeut. 17 (2018) 2551-2563. https://doi.org/10.1158/1535-7163.MCT-18-0177.

[67]	K. Strebhardt, A. Ullrich, Targeting polo-like kinase 1 for cancer therapy, Nat. Rev. Cancer 6 (2006) 321-330. https://doi.org/10.1038/nrc1841.

[68]	L. Kozlovskaya, M. Abou-Kaoud, D. Stepensky, Quantitative analysis of drug delivery to the brain via nasal route, J. Contr. Release 189 (2014) 133-140. https://doi.org/10.1016/j.jconrel.2014.06.053.

[69]	H. Pan, H. Wang, Y. Jia, Q. Wang, L. Li, Q. Wu, L. Chen, VPA and MEL induce apoptosis by inhibiting the Nrf2-ARE signaling pathway in TMZ-resistant U251 cells, Mol. Med. Rep. 16 (2017) 908-914. https://doi.org/10.3892/mmr.2017.6621.

[70]

N. Salazar, J.C. Carlson, K. Huang, Y. Zheng, C. Oderup, J. Gross, A.D. Jang, T.M. Burke, S. Lewen, A. Scholz, S. Huang, L. Nease, J. Kosek, M. Mittelbronn, E.C. Butcher, H. Tu, B.A. Zabel, A chimeric antibody against ACKR3/CXCR7 in combination with TMZ activates immune responses and extends survival in mouse GBM models, Mol. Ther. 26 (2018) 1354-1365. https://doi.org/10.1016/j.ymthe.2018.02.030.

[71]

S.B. Jeong, J.H. Im, J.H. Yoon, Q.T. Bui, S.C. Lim, J.M. Song, Y. Shim, J. Yun, J. Hong, K.W. Kang, Essential role of polo-like kinase 1 (Plk1) oncogene in tumor growth and metastasis of tamoxifen-resistant breast cancer, Mol. Cancer Therapeut. 17 (2018) 825-837. https://doi.org/10.1016/j.bcp.2021.114747.

[72]	A.L. Bolcato-Bellemin, M.E. Bonnet, G. Creusat, P. Erbacher, J.P. Behr, Sticky overhangs enhance siRNA-mediated gene silencing, Proc. Natl. Acad. Sci. USA 104 (2007) 16050-16055. https://doi.org/10.1073/pnas.0707831104.

[73]	K. Buyens, M. Meyer, E. Wagner, J. Demeester, S.C. De Smedt, N.N. Sanders, Monitoring the disassembly of siRNA polyplexes in serum is crucial for predicting their biological efficacy, J. Contr. Release 141 (2010) 38-41. https://doi.org/10.1016/j.jconrel.2009.08.026.

[74]	A. Alama, A.M. Orengo, S. Ferrini, R. Gangemi, Targeting cancer-initiating cell drug-resistance: a roadmap to a new-generation of cancer therapies? Drug Discov. Today 17 (2012) 435-442. https://doi.org/10.1016/j.drudis.2011.02.005.

[75]

H. Guvenc, M.S. Pavlyukov, K. Joshi, H. Kurt, Y.K. Banasavadi-Siddegowda, P. Mao, C. Hong, R. Yamada, C.H. Kwon, D. Bhasin, S. Chettiar, G. Kitange, I.H. Park, J.N. Sarkaria, C. Li, M.I. Shakhparonov, I. Nakano, Impairment of glioma stem cell survival and growth by a novel inhibitor for Survivin-Ran protein complex, Clin. Cancer Res. 19 (2013) 631-642. https://doi.org/10.1158/1078-0432.CCR-12-0647.

[76]	R. Kar, J.K. Palanichamy, A. Banerjee, P. Chattopadhyay, S.K. Jain, N. Singh, Survivin siRNA increases sensitivity of primary cultures of ovarian cancer cells to paclitaxel, Clin. Transl. Oncol. 17 (2015) 737-742. https://doi.org/10.1007/s12094-015-1302-2.

[77]

B.J. Curtis, N.J. Niemuth, E. Bennett, A. Schmoldt, O. Mueller, A.A. Mohaimani, E.D. Laudadio, Y. Shen, J.C. White, R.J. Hamers, R.D. Klaper, Cross-species transcriptomic signatures identify mechanisms related to species sensitivity and common responses to nanomaterials, Nat. Nanotechnol. 17 (2022) 661-669. https://doi.org/10.1038/s41565-022-01096-2.

[78]	J.W. Lee, J. Choi, Y. Choi, K. Kim, Y. Yang, S.H. Kim, H.Y. Yoon, I.C. Kwon, Molecularly engineered siRNA conjugates for tumor-targeted RNAi therapy, J. Contr. Release 351 (2022) 713-726. https://doi.org/10.1016/j.jconrel.2022.09.040.

[79]	C.W. Tsao, A.W. Aday, Z.I. Almarzooq, Heart disease and stroke statistics-2022 update: a report from the American Heart Association, Circulation 145 (2022) e153-e639. https://doi.org/10.1161/cir.0000000000001052.

[80]	S.S. Virani, A. Alonso, E.J. Benjamin, M.S. Bittencourt, C.W. Callaway, Heart disease and stroke statistics-2020 update: a report from the American Heart Association, Circulation 141 (2020) e139-e596. https://doi.org/10.1161/CIR.0000000000000757.

[81]

W.J. Powers, A.A. Rabinstein, T. Ackerson, O.M. Adeoye, N.C. Bambakidis, K. Becker, J. Biller, M. Brown, B.M. Demaerschalk, B. Hoh, E.C. Jauch, C.S. Kidwell, T.M. Leslie-Mazwi, B. Ovbiagele, P.A. Scott, K.N. Sheth, A.M. Southerland, D.V. Summers, D.L. Tirschwell, Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association, Stroke 50 (2019) e344-e418. https://doi.org/10.1161/STR.0000000000000211.

[82]

H.P. Adams Jr., G.del Zoppo, Guidelines for the early management of adults with ischemic stroke - a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the atherosclerotic peripheral vascular disease and quality of care outcomes in research interdisciplinary working groups, Stroke 38 (2007) 1655-1711, https://doi.org/10.1161/STROKEAHA.107.181486.

[83]

M. Fiorelli, S. Bastianello, R. von Kummer, G.J. del Zoppo, V. Larrue, E. Lesaffre, A.P. Ringleb, S. Lorenzano, C. Manelfe, L. Bozzao, Hemorrhagic transformation within 36 hours of a cerebral infarct: relationships with early clinical deterioration and 3-month outcome in the European Cooperative Acute Stroke Study I (ECASS I) cohort, Stroke 30 (1999) 2280-2284. https://doi.org/10.1161/01.STR.30.11.2280.

[84]

J. Xu, Y. Zhang, J. Xu, G. Liu, C. Di, X. Zhao, X. Li, Y. Li, N. Pang, C. Yang, Y. Li, B. Li, Z. Lu, M. Wang, K. Dai, R. Yan, S. Li, G. Nie, Engineered nanoplatelets for targeted delivery of plasminogen activators to reverse thrombus in multiple mouse thrombosis models, Adv. Mater. 32 (2020) e1905145. https://doi.org/10.1002/adma.201905145.

[85]	J. Anrather, C. Iadecola, Inflammation and stroke: an overview, Neurotherapeutics 13 (2016) 661-670. https://doi.org/10.1007/s13311-016-0483-x.

[86]	Q.Z. Tuo, S.T. Zhang, P. Lei, Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications, Med. Res. Rev. 42 (2022) 259-305. https://doi.org/10.1002/med.21817.

[87]	T. Ganbold, Q. Bao, J. Zandan, A. Hasi, H. Baigude, Modulation of microglia polarization through silencing of NF-kappaB p65 by functionalized curdlan nanoparticle-mediated RNAi, ACS Appl. Mater. Interfaces 12 (2020) 11363-11374. https://doi.org/10.1021/acsami.9b23004.

[88]	T. Ganbold, Q. Bao, H. Xiao, D. Zurgaanjin, C. Liu, S. Han, A. Hasi, H. Baigude, Peptidomimetic lipid-nanoparticle-mediated knockdown of TLR4 in CNS protects against cerebral ischemia/reperfusion injury in mice, Nanomaterials 12 (2022) 2027. https://doi.org/10.3390/nano12122072.

[89]	L. Lu, Y. Wang, F. Zhang, M. Chen, B. Lin, X. Duan, M. Cao, C. Zheng, J. Mao, X. Shuai, J. Shen, MRI-visible siRNA nanomedicine directing neuronal differentiation of neural stem cells in stroke, Adv. Funct. Mater. 28 (2018) 1706769. https://doi.org/10.1002/adfm.201706769.

[90]

B. Lin, L. Lu, Y. Wang, Q. Zhang, Z. Wang, G. Cheng, X. Duan, F. Zhang, M. Xie, H. Le, X. Shuai, J. Shen, Nanomedicine directs neuronal differentiation of neural stem cells via silencing long noncoding RNA for stroke therapy, Nano Lett. 21 (2021) 806-815. https://doi.org/10.1021/acs.nanolett.0c04560.

[91]

C. Wang, G. Lin, Y. Luan, J. Ding, P.C. Li, Z. Zhao, C. Qian, G. Liu, S. Ju, G.J. Teng, HIF-prolyl hydroxylase 2 silencing using siRNA delivered by MRI-visible nanoparticles improves therapy efficacy of transplanted EPCs for ischemic stroke, Biomaterials 197 (2019) 229-243. https://doi.org/10.1016/j.biomaterials.2018.05.053.

[92]

T. Kanazawa, T. Kurano, H. Ibaraki, Y. Takashima, T. Suzuki, Y. Seta, Therapeutic effects in a transient middle cerebral artery occlusion rat model by nose-to-brain delivery of anti-TNF-Alpha siRNA with cell-penetrating peptide-modified polymer micelles, Pharmaceutics 11 (2019) 478. https://doi.org/10.3390/pharmaceutics11090478.

[93]

S.G. Choi, J. Shin, K.Y. Lee, H. Park, S.I. Kim, Y.Y. Yi, D.W. Kim, H.J. Song, H.J. Shin, PINK 1 siRNA-loaded poly(lactic-co-glycolic acid) nanoparticles provide neuroprotection in a mouse model of photothrombosis-induced ischemic stroke, Glia 71 (2023) 1294-1310. https://doi.org/10.1002/glia.24339.

[94]	X.Y. Xiong, L. Liu, Q.W. Yang, Functions and mechanisms of microglia/ macrophages in neuroinflammation and neurogenesis after stroke, Prog. Neurobiol. 142 (2016) 23-44. https://doi.org/10.1016/j.pneurobio.2016.05.001.

[95]	T. Liu, L. Zhang, D. Joo, S.C. Sun, NF-kappaB signaling in inflammation, Signal Transduct, Targeted Ther. 2 (2017) 17023. https://doi.org/10.1038/sigtrans.2017.23.

[96]	F. Wang, Y. Zhu, The interaction of Nogo-66 receptor with Nogo-p4 inhibits the neuronal differentiation of neural stem cells, Neuroscience 151 (2008) 74-81. https://doi.org/10.1016/j.neuroscience.2007.10.034.

[97]	X. Li, Q.L. Fu, X.L. Jing, X.X. Liao, A.H. Zeng, Y. Xiong, X.X. Liao, Myelinassociated glycoprotein inhibits the neuronal differentiation of neural progenitors, Neuroreport 20 (2009) 708-712. https://doi.org/10.1097/WNR.0b013e32832aa942.

[98]

A.D. Ramos, R.E. Andersen, S.J. Liu, T.J. Nowakowski, S.J. Hong, C. Gertz, R.D. Salinas, H. Zarabi, A.R. Kriegstein, D.A. Lim, The long noncoding RNA Pnky regulates neuronal differentiation of embryonic and postnatal neural stem cells, Cell Stem Cell 16 (2015) 439-447. https://doi.org/10.1016/j.stem.2015.02.007.

[99]

T. Shichita, E. Hasegawa, A. Kimura, R. Morita, R. Sakaguchi, I. Takada, T. Sekiya, H. Ooboshi, T. Kitazono, T. Yanagawa, T. Ishii, H. Takahashi, S. Mori, M. Nishibori, K. Kuroda, S. Akira, K. Miyake, A. Yoshimura, Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain, Nat. Med. 18 (2012) 911-917. https://doi.org/10.1038/nm.2749.

[100]

E.M. Fivenson, S. Lautrup, N. Sun, M. Scheibye-Knudsen, T. Stevnsner, H. Nilsen, V.A. Bohr, E.F. Fang, Mitophagy in neurodegeneration and aging, Neurochem. Int. 109 (2017) 202-209. https://doi.org/10.1016/j.neuint.2017.02.007.

[101]

Z. Shao, S. Dou, J. Zhu, H. Wang, D. Xu, C. Wang, B. Cheng, B. Bai, The role of mitophagy in ischemic stroke, Front. Neurol. 11 (2020) 608610. https://doi. org/10.3389/fneur.2020.608610.

[102]

X. Zheng, X. Pang, P. Yang, X. Wan, Y. Wei, Q. Guo, Q. Zhang, X. Jiang, A hybrid siRNA delivery complex for enhanced brain penetration and precise amyloid plaque targeting in Alzheimer’s disease mice, Acta Biomater. 49 (2017) 388-401. https://doi.org/10.1016/j.actbio.2016.11.029.

[103]

R. Zhang, Y. Li, B. Hu, Z. Lu, J. Zhang, X. Zhang, Traceable nanoparticle delivery of small interfering RNA and retinoic acid with temporally release ability to control neural stem cell differentiation for Alzheimer’s disease therapy, Adv. Mater. 28 (2016) 6345-6352. https://doi.org/10.1002/adma.201600554.

[104]

S. Singh Kamaljeet, G.D. Gupta, K.R. Aran, Emerging role of antioxidants in Alzheimer’s disease: insight into physiological, pathological mechanisms and management, Pharmaceut. Sci. Adv. 2 (2024) 100021. https://doi.org/10.1016/j.pscia.2023.100021.

[105]

D. Yu, M. Ma, Z. Liu, Z. Pi, X. Du, J. Ren, X. Qu, MOF-encapsulated nanozyme enhanced siRNA combo: control neural stem cell differentiation and ameliorate cognitive impairments in Alzheimer’s disease model, Biomaterials 255 (2020) 120160. https://doi.org/10.1016/j.biomaterials.2020.120160.

[106]

P. Wang, X. Zheng, Q. Guo, P. Yang, X. Pang, K. Qian, W. Lu, Q. Zhang, X. Jiang, Systemic delivery of BACE1 siRNA through neuron-targeted nanocomplexes for treatment of Alzheimer’s disease, J. Contr. Release 279 (2018) 220-233. https://doi.org/10.1016/j.jconrel.2018.04.034.

[107]

M. Imran Sajid, F. Sultan Sheikh, F. Anis, N. Nasim, R.K. Sumbria, S.M. Nauli, R. Kumar Tiwari, siRNA drug delivery across the blood-brain barrier in Alzheimer’s disease, Adv. Drug Deliv. Rev. 199 (2023) 114968. https://doi.o rg/10.1016/j.addr.2023.114968.

[108]

C. Kurz, L. Walker, B.S. Rauchmann, R. Perneczky, Dysfunction of the blood-brain barrier in Alzheimer’s disease: evidence from human studies, Neuropathol. Appl. Neurobiol. 48 (2022) e12782. https://doi.org/10.1111/nan.12782.

[109]

T.E. Park, B. Singh, H. Li, J.Y. Lee, S.K. Kang, Y.J. Choi, C.S. Cho, Enhanced BBB permeability of osmotically active poly(mannitol-co-PEI) modified with rabies virus glycoprotein via selective stimulation of caveolar endocytosis for RNAi therapeutics in Alzheimer’s disease, Biomaterials 38 (2015) 61-71. https://doi.org/10.1016/j.biomaterials.2014.10.068.

[110]

G. Rassu, E. Soddu, A.M. Posadino, G. Pintus, B. Sarmento, P. Giunchedi, E. Gavini, Nose-to-brain delivery of BACE1 siRNA loaded in solid lipid nanoparticles for Alzheimer’s therapy, Colloids Surf. B Biointerfaces 152 (2017) 296-301. https://doi.org/10.1016/j.colsurfb.2017.01.031.

[111]

A.D. Tagalakis, D.H. Lee, A.S. Bienemann, H. Zhou, M.M. Munye, L. Saraiva, D. McCarthy, Z. Du, C.A. Vink, R. Maeshima, E.A. White, K. Gustafsson, S.L. Hart, Multifunctional, self-assembling anionic peptide-lipid nanocomplexes for targeted siRNA delivery, Biomaterials 35 (2014) 8406-8415. https://doi.org/10.1016/j.biomaterials.2014.06.003.

[112]

H. Xu, Y. Liu, ROS-responsive nanomodulators downregulate IFITM3 expression and eliminate ROS for Alzheimer’s disease combination treatment, J. Colloid Interface Sci. 645 (2023) 210-218. https://doi.org/10.1016/j.jcis.2023.04.139.

[113]

R. Yan, R. Vassar, Targeting the beta secretase BACE1 for Alzheimer’s disease therapy, Lancet Neurol. 13 (2014) 319-329. https://doi.org/10.1016/S1474-4422(13)70276-X.

[114]

J.Y. Hur, G.R. Frost, X. Wu, C. Crump, S.J. Pan, E. Wong, M. Barros, T. Li, P. Nie, Y. Zhai, J.C. Wang, J. Tcw, L. Guo, A. McKenzie, C. Ming, X. Zhou, M. Wang, Y. Sagi, A.E. Renton, B.T. Esposito, Y. Kim, K.R. Sadleir, I. Trinh, R.A. Rissman, R. Vassar, B. Zhang, D.S. Johnson, E. Masliah, P. Greengard, A. Goate, Y.M. Li, The innate immunity protein IFITM3 modulates gamma-secretase in Alzheimer’s disease, Nature 586 (2020) 735-740. https://doi.org/10.1038/s41586-020-2681-2.

[115]

S.W. Wang, Y.J. Wang, Y.J. Su, W.W. Zhou, S.G. Yang, R. Zhang, M. Zhao, Y.N. Li, Z.P. Zhang, D.W. Zhan, R.T. Liu, Rutin inhibits beta-amyloid aggregation and cytotoxicity, attenuates oxidative stress, and decreases the production of nitric oxide and proinflammatory cytokines, Neurotoxicology 33 (2012) 482-490. https://doi.org/10.1016/j.neuro.2012.03.003.

[116]

Y. Chen, B. Zhang, L. Yu, J. Zhang, Y. Zhao, L. Yao, H. Yan, W. Tian, A novel nanoparticle system targeting damaged mitochondria for the treatment of Parkinson’s disease, Biomater. Adv. 138 (2022) 212876. https://doi.org/10.1016/j.bioadv.2022.212876.

[117]

X. Niu, J. Chen, J. Gao, Nanocarriers as a powerful vehicle to overcome bloodbrain barrier in treating neurodegenerative diseases: focus on recent advances, Asian J. Pharm. Sci. 14 (2019) 480-496. https://doi.org/10.1016/j.ajps.2018.09.005.

[118]

S. Tang, A. Wang, X. Yan, L. Chu, X. Yang, Y. Song, K. Sun, X. Yu, R. Liu, Z. Wu, P. Xue, Brain-targeted intranasal delivery of dopamine with borneol and lactoferrin co-modified nanoparticles for treating Parkinson’s disease, Drug Deliv. 26 (2019) 700-707. https://doi.org/10.1080/10717544.2019.1636420.

[119]

P. Haussermann, W. Kuhn, H. Przuntek, T. Muller, Integrity of the bloodcerebrospinal fluid barrier in early Parkinson’s disease, Neurosci. Lett. 300 (2001) 182-184. https://doi.org/10.1016/S0304-3940(01)01574-9.

[120]

H. Cortes, S. Alcala-Alcala, A. Avalos-Fuentes, N. Mendoza-Munoz, D. Quintanar- Guerrero, G. Leyva-Gomez, B. Floran, Nanotechnology as potential tool for siRNA delivery in Parkinson’s disease, Curr. Drug Targets 18 (2017) 1866-1879. https://doi.org/10.2174/1389450118666170321130003.

[121]

S.F. Liu, L.Y. Li, J.L. Zhuang, M.M. Li, L.C. Ye, X.R. Chen, S. Lin, C.N. Chen, Update on the application of mesenchymal stem cell-derived exosomes in the treatment of Parkinson’s disease: a systematic review, Front. Neurol. 13 (2022) 950715. https://doi.org/10.3389/fneur.2022.950715.

[122]

H. Kebir, K. Kreymborg, I. Ifergan, A. Dodelet-Devillers, R. Cayrol, M. Bernard, F. Giuliani, N. Arbour, B. Becher, A. Prat, Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation, Nat. Med. 13 (2007) 1173-1175. https://doi.org/10.1038/nm1651.

[123]

W.M. Pardridge, Blood-brain barrier and delivery of protein and gene therapeutics to brain, Front. Aging Neurosci. 11 (2020) 373. https://doi.org/10.3389/fnagi.2019.00373.

[124]

J. Kang, J. Joo, E.J. Kwon, M. Skalak, S. Hussain, Z.G. She, E. Ruoslahti, S.N. Bhatia, M.J. Sailor, Self-sealing porous silicon-calcium silicate core-shell nanoparticles for targeted siRNA delivery to the injured brain, Adv. Mater. 28 (2016) 7962-7969. https://doi.org/10.1002/adma.201600634.

[125]

W. Li, J. Qiu, X.L. Li, S. Aday, J. Zhang, G. Conley, J. Xu, J. Joseph, H. Lan, R. Langer, R. Mannix, J.M. Karp, N. Joshi, BBB pathophysiology-independent delivery of siRNA in traumatic brain injury, Sci. Adv. 7 (2021) eabd6889. https://doi.org/10.1126/sciadv.abd6889.

[126]

V. Sava, O. Fihurka, A. Khvorova, J. Sanchez-Ramos, Enriched chitosan nanoparticles loaded with siRNA are effective in lowering Huntington’s disease gene expression following intranasal administration, Nanomedicine 24 (2020) 102119. https://doi.org/10.1016/j.nano.2019.102119.

[127]

M.C. Didiot, L.M. Hall, A.H. Coles, R.A. Haraszti, B.M. Godinho, K. Chase, E. Sapp, S. Ly, J.F. Alterman, M.R. Hassler, D. Echeverria, L. Raj, D.V. Morrissey, M. DiFiglia, N. Aronin, A. Khvorova, Exosome-mediated delivery of hydrophobically modified siRNA for huntingtin mRNA silencing, Mol. Ther. 24 (2016) 1836-1847. https://doi.org/10.1038/mt.2016.126.

[128]

A. Holm, S.N. Hansen, H. Klitgaard, S. Kauppinen, Clinical advances of RNA therapeutics for treatment of neurological and neuromuscular diseases, RNA Biol. 19 (2022) 594-608. https://doi.org/10.1080/15476286.2022.2066334.