基因治疗中的核酸药物及非病毒递送载体的研究进展

doi:10.16352/j.issn.1001-6325.2022.01.002

摘要/Abstract

摘要： 基因治疗是针对基因异常相关疾病的终极治疗技术,各种具有不同机制的核酸药物的出现为基因治疗带来了更多的可能性。但是,由于存在体内稳定性差、难以高效进入靶细胞等问题,核酸药物需要载体的帮助而进入目标细胞并到达特定的胞内位置,因此,开发安全高效的核酸递送系统是基因治疗的基石。与病毒载体相比,非病毒载体具有更高的安全性,但转染效率较低。随着纳米技术的发展,非病毒载体的效率得到了显著的提升,进入临床研究的数量逐渐增多。本文简要介绍基因治疗中的核酸药物及其递送载体,对非病毒核酸药物递送技术的瓶颈及进展做综合评述。

关键词: 基因治疗, 核酸药物, 非病毒载体, 药物递送系统

Abstract: Gene therapy based on nucleic acid drugs is the ultimate treatment technology for gene abnormality related diseases. However, nucleic acid drugs need the help of carriers to enter target cells and reach specific intracellular locations, therefore, the development of safe and efficient delivery systems for nucleic acid drugs is one of the fundamental technologies for gene therapy. Compared with viral vectors, non-viral vectors have higher safety, but are still facing the challenge of relative low transfection efficiency. With the advances of nanotechnology, the efficiency of non-viral carriers has been gained significantly improvements. In this paper, some representative nucleic acid-based drugs and vaccines are introduced, and the progresses of non-viral delivery carriers for uses in gene therapy have been reviewed.

Key words: gene therapy, nucleic acid drugs, non-viral carrier, drug delivery system

中图分类号:

Q782

刘健. 基因治疗中的核酸药物及非病毒递送载体的研究进展[J]. 基础医学与临床, 2022, 42(1): 41-50.

LIU Jian. Progress of nucleic acid drugs and non-viral carriers in gene therapy[J]. Basic & Clinical Medicine, 2022, 42(1): 41-50.

参考文献

[1]Winn SR, Hu Y, Sfeir C, et al. Gene therapy approaches for modulating bone regeneration[J]. Adv Drug Deliv Rev, 2000, 42: 121-138.
[2]Chen C, Yang Z, Tang X. Chemical modifications of nucleic acid drugs and their delivery systems for gene-based therapy[J]. Med Res Rev, 2018, 38: 829-869.
[3]Zamore PD, Tuschl T, Sharp PA, et al. RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals[J]. Cell, 2000, 101: 25-33.
[4]Setten RL, Rossi JJ, Han SP. The current state and future directions of RNAi-based therapeutics[J]. Nat Rev Drug Discov, 2019, 18: 421-446.
[5]Saw PE, Song EW. siRNA therapeutics: a clinical reality[J]. Sci China Life Sci, 2020, 63: 485-500.
[6]Scott LJ, Keam SJ. Lumasiran: first approval[J]. Drugs, 2021, 81: 277-282.
[7]Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia[J]. N Engl J Med, 2020, 382: 1520-1530.
[8]Gharanei S, Shabir K, Brown JE, et al. Regulatory microRNAs in brown, brite and white adipose tissue[J]. Cells, 2020, 9, 2489. doi: 10.3390/cells9112489.
[9]Miller T, Cudkowicz M, Shaw PJ, et al. Phase 1-2 trial of antisense oligonucleotide tofersen for SOD1 ALS[J]. N Engl J Med, 2020, 383: 109-119.
[10]Shimamura M, Morishita R. Naked plasmid DNA for gene therapy[J]. Curr Gene Ther, 2011, 11: 433. doi: 10.2174/156652311798192824.
[11]Baden LR, EL Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine[J]. N Engl J Med, 2021, 384: 403-416.
[12]Wang X. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine[J]. N Engl J Med, 2021, 384: 1577-1578.
[13]Blass E, Ott PA. Advances in the development of personalized neoantigen-based therapeutic cancer vaccines[J]. Nat Rev Clin Oncol, 2021, 18: 215-229.
[14]Omer L, Hudson EA, Zheng S, et al. CRISPR correction of a homozygous low-density lipoprotein receptor mutation in familial hypercholesterolemia induced pluripotent stem cells[J]. Hepatol Commun, 2017, 1: 886-898.
[15]Bengtsson NE, Hall JK, Odom GL, et al. Muscle-specific CRISPR/Cas9 dystrophin gene editing ameliorates pathophysiology in a mouse model for Duchenne muscular dystrophy[J]. Nat Commun, 2017, 8: 14454. doi: 10.1038/ncomms14454.
[16]Yin H, Kauffman KJ, Anderson DG. Delivery technologies for genome editing[J]. Nat Rev Drug Discov, 2017, 16: 387-399.
[17]Wilbie D, Walther J, Mastrobattista E. Delivery aspects of CRISPR/Cas for in vivo genome editing[J]. Acc Chem Res, 2019, 52: 1555-1564.
[18]Liu J, Chang J, Jiang Y, et al. Fast and efficient CRISPR/Cas9 genome editing in vivo enabled by bioreducible lipid and messenger RNA nanoparticles[J]. Adv Mater, 2019, 31: e1902575. doi: 10.1002/adma.201902575.
[19]Finer M, Glorioso J. A brief account of viral vectors and their promise for gene therapy[J]. Gene Ther, 2017, 24: 1-2.
[20]Shirley JL, De Jong YP, Terhorst C, et al. Immune responses to viral gene therapy vectors[J]. Mol Ther, 2020, 28: 709-722.
[21]Mohammadinejad R, Dehshahri A, Sagar Madamsetty V, et al. In vivo gene delivery mediated by non-viral vectors for cancer therapy[J]. J Control Release, 2020, 325: 249-275.
[22]Wojnilowicz M, Glab A, Bertucci A, et al. Super-resolution imaging of proton sponge-triggered rupture of endosomes and cytosolic release of small interfering RNA[J]. ACS Nano, 2019, 13: 187-202.
[23]Zhi D, Bai Y, Yang J, et al. A review on cationic lipids with different linkers for gene delivery[J]. Adv Colloid Interface Sci, 2018, 253: 117-140.
[24]Ponti F, Campolungo M, Melchiori C, et al. Cationic lipids for gene delivery: many players, one goal[J]. Chem Phys Lipids, 2021, 235: 105032. doi: 10.1016/j.chemphyslip.2020.105032.
[25]Mochizuki S, Kanegae N, Nishina K, et al. The role of the helper lipid dioleoylphosphatidylethanolamine (DOPE) for DNA transfection cooperating with a cationic lipid bearing ethylenediamine[J]. Biochim Biophys Acta, 2013, 1828: 412-418.
[26]Ho W, Gao M, Li F, et al. Next-generation vaccines: nanoparticle-mediated DNA and mRNA delivery[J]. Adv Healthc Mater, 2021, 10: e2001812. doi: 10.1002/adhm.202001812.
[27]Akinc A, Maier MA, Manoharan M, et al. The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs[J]. Nat Nanotechnol, 2019, 14: 1084-1087.
[28]Finn JD, Smith AR, Patel MC, et al. A single administration of CRISPR/Cas9 lipid nanoparticles achieves robust and persistent in vivo genome editing[J]. Cell Rep, 2018, 22: 2227-2235.
[29]Wang J, Ye X, Ni H, et al. Transfection efficiency evaluation and endocytosis exploration of different polymer condensed agents[J]. DNA Cell Biol, 2019, 38: 1048-1055.
[30]Dias AP, Da Silva Santos S, Da Silva JV, et al. Dendrimers in the context of nanomedicine[J]. Int J Pharm, 2020, 573: 118814. doi: 10.1016/j.ijpharm.2019.118814.
[31]Cai JG, Yue YA, Rui D, et al. Effect of chain length on cytotoxicity and endocytosis of cationic polymers[J]. Macromolecules, 2011, 44: 2050-2057.
[32]Ding GB, Meng X, Yang P, et al. Integration of polylactide into polyethylenimine facilitates the safe and effective intracellular siRNA delivery[J]. Polymers (Basel), 2020, 12: 445. doi: 10.3390/polym12020445.
[33]Wu XR, Zhang J, Zhang JH, et al. Amino acid-linked low molecular weight polyethylenimine for improved gene delivery and biocompatibility[J]. Molecules, 2020, 25: 975. doi: 10.3390/molecules25040975.
[34]Yin L, Yuvienco C, Montclare JK. Protein based therapeutic delivery agents: Contemporary developments and challenges[J]. Biomaterials, 2017, 134: 91-116.
[35]Thomas TJ, Tajmir-Riahi HA, Pillai C KS. Biodegradable polymers for gene delivery[J]. Molecules, 2019, 24: 3744. doi: 10.3390/molecules24203744.
[36]Mohammadi Z, Eini M, Rastegari A, et al. Chitosan as a machine for biomolecule delivery: A review[J]. Carbohydr Polym, 2021, 256: 117414. doi: 10.1016/j.carbpol.2020.117414.
[37]Messerschmidt VL, Chintapulau, Kuriakose AE, et al. Notch intracellular domain plasmid delivery via poly(lactic-co-glycolic acid) nanoparticles to upregulate Notch pathway molecules[J]. Front Cardiovasc Med, 2021, 8: 707897. doi: 10.3389/fcvm.2021.707897.
[38]Riley MK, Vermerris W. Recent advances in nanomaterials for gene delivery-a review[J]. Nanomaterials (Basel), 2017, 7: 94. doi: 10.3390/nano7050094.
[39]Mohammadinejad R, Dadashzadeh A, Moghassemi S, et al. Shedding light on gene therapy: Carbon dots for the minimally invasive image-guided delivery of plasmids and noncoding RNAs-A review[J]. J Adv Res, 2019, 18: 81-93.
[40]Blokpoel Ferreras LA, Chan SY, Vazquez Reina S, et al. Rapidly transducing and spatially localized magnetofection using peptide-mediated non-viral gene delivery based on iron oxide nanoparticles[J]. ACS Appl Nano Mater, 2021, 4: 167-181.
[41]Alvizo-Baez CA, Luna-Cruz IE, Vilches-Cisneros N, et al. Systemic delivery and activation of the TRAIL gene in lungs, with magnetic nanoparticles of chitosan controlled by an external magnetic field[J]. Int J Nanomedicine, 2016, 11: 6449-6458.
[42]Wang P, Zhang L, Zheng W, et al. Thermo-triggered release of CRISPR-Cas9 system by lipid-encapsulated gold nanoparticles for tumor therapy[J]. Angew Chem Int Ed Engl, 2018, 57: 1491-1496.
[43]Liu Y, Xx M, Zhao Y, et al. Flower-like gold nanoparticles for enhanced photothermal anticancer therapy by the delivery of pooled siRNA to inhibit heat shock stress response[J]. J Mater Chem B, 2019, 7: 586-597.
[44]Kalluri R, Lebleu VS. The biology, function, and biomedical applications of exosomes[J]. Science, 2020, 367: eaau6977. doi: 10.1126/science.aau6977.
[45]Duan L, Xu L, Xu X, et al. Exosome-mediated delivery of gene vectors for gene therapy[J]. Nanoscale, 2021, 13: 1387-1397.
[46]Willibald J, Harder J, Sparrer K et al. Click-modified anandamide siRNA enables delivery and gene silencing in neuronal and immune cells[J]. J Am Chem Soc, 2012, 134: 12330-12333.
[47]Springer AD, Dowdy SF. GalNAc-siRNA conjugates: leading the way for delivery of RNAi therapeutics[J]. Nucleic Acid Ther, 2018, 28: 109-118.
[48]Nair JK, Attarwala H, Sehgal, et al. Impact of enhanced metabolic stability on pharmacokinetics and pharmacodynamics of GalNAc-siRNA conjugates[J]. Nucleic Acids Res, 2017, 45: 10969-10977.
[49]Aalim L, Islam G, Desaulniers JP. Targeted delivery and enhanced gene-silencing activity of centrally modified folic acid-siRNA conjugates[J]. Nucleic Acids Res, 2020, 48: 75-85.
[50]Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery[J]. Nat Biotechnol, 2015, 33: 941-951.
[51]Suk JS, Xu Q, Kim N, et al. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery[J]. Adv Drug Deliv Rev, 2016, 99(Pt A): 28-51.
[52]Del Prado A,Civantos A, Martinez-Campos E, et al. Efficient and low cytotoxicity gene carriers based on amine-functionalized polyvinylpyrrolidone[J]. Polymers (Basel), 2020, 12: 2724. doi: 10.3390/polym12112724.
[53]Lee Y, Lee J, Kim M, et al. Brain gene delivery using histidine and arginine-modified dendrimers for ischemic stroke therapy[J]. J Control Release, 2021, 330: 907-919.
[54]Qiu Y, Tong S, Zhang L, et al. Magnetic forces enable controlled drug delivery by disrupting endothelial cell-cell junctions[J]. Nat Commun, 2017, 8: 15594. doi: 10.1038/ncomms15594.
[55]Xiong X, Xu Z, Huang H, et al. A NIR light triggered disintegratable nanoplatform for enhanced penetration and chemotherapy in deep tumor tissues[J]. Biomaterials, 2020, 245: 119840. doi: 10.1016/j.biomaterials.2020.119840.
[56]Liu Y, Huo Y, Yao L, et al. Transcytosis of nanomedic-ine for tumor penetration[J]. Nano Lett, 2019, 19: 8010-8020.
[57]Du X, Wang J, Zhou Q, et al. Advanced physical techniques for gene delivery based on membrane perforation[J]. Drug Deliv, 2018, 25: 1516-1525.
[58]Dimcevski G, Kotopoulis S, Bjanes T, et al. A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer[J]. J Control Release, 2016, 243: 172-181.
[59]Wang J, Xie L, Wang T, et al. Visible light-switched cytosol release of siRNA by amphiphilic fullerene derivative to enhance RNAi efficacy in vitro and in vivo[J]. Acta Biomater, 2017, 59: 158-169.
[60]Brock DJ, Kondow-Mcconaghy HM, Hager EC, et al. Endosomal escape and cytosolic penetration of macro-molecules mediated by synthetic delivery agents[J]. Bioconjugate Chem, 2019, 30: 293-304.
[61]Sun W, Davis PB. Reducible DNA nanoparticles enhance in vitro gene transfer via an extracellular mechanism[J]. J Control Release, 2010, 146: 118-127.
[62]Nie JJ, Liu Y, Qi Y, et al. Charge-reversal nanocomolexes-based CRISPR/Cas9 delivery system for loss-of-func-tion oncogene editing in hepatocellular carcinoma[J]. J Control Release, 2021, 333: 362-373.
[63]Fang Y, Lin X, Jin X, et al. Design and fabrication of dual redox responsive nanoparticles with diselenide linkage combined photodynamically to effectively enhance gene expression[J]. Int J Nanomedicine, 2020, 15: 7297-7314.
[64]Bai H, Lester GMS, Petishnok LC, et al. Cytoplasmic transport and nuclear import of plasmid DNA[J]. Biosci Rep, 2017, 37: BSR20160616. doi: 10.1042/BSR20160616.
[65]Tan G, Liu D, Zhu R, et al. A core-shell nanoplatform as a nonviral vector for targeted delivery of genes to the retina[J]. Acta Biomater, 2021, 134: 605-620.
[66]Palchetti S, Digiacomo L, Giulimondi F, et al. A mechanistic explanation of the inhibitory role of the protein corona on liposomal gene expression[J]. Biochim Biophys Acta Biomembr, 2020, 1862: 183159. doi: 10.1016/j.bbamem.2019.183159.
[67]Zhang W, Meng X, Liu H, et al. Ratio of polycation and serum is a crucial index for determining the RNAi efficiency of polyplexes[J]. ACS Appl Mater Interfaces, 2017, 9: 43529-43537.
[68]Cagliani R, Gatto F, Bardi G. Protein adsorption: a feasible method for nanoparticle functionalization?[J]. Materials (Basel), 2019, 12: 1991. doi: 10.3390/ma12121991.

编辑推荐 0

Metrics

阅读次数

全文

1342

HTML			PDF

最新录用	在线预览	正式出版	最新录用	在线预览	正式出版
0	0	0	0	0	1342

来源	本网站	其他网站

次数	914	428
比例	68%	32%

摘要

1195

最新录用	在线预览	正式出版

0	0	1195

来源	本网站	其他网站

次数	1166	29
比例	98%	2%