Abstract
In recent years, mesenchymal stem cells (MSCs) as a new tool for therapeutic gene delivery in clinics have attracted much attention. Their advantages cover longer lifespan, better isolation, and higher transfection efficiency and proliferation rate. MSCs are the preferred approach for cell-based therapies because of their in vitro self-renewal capacity, migrating especially to tumor tissues, as well as anti-inflammatory and immunomodulatory properties. Therefore, they have considerable efficiency in genetic engineering for future clinical applications in cancer gene therapy and other diseases. For improving therapeutic efficiency, targeted therapy of cancers can be achieved through the sustained release of therapeutic agents and functional gene expression induction to the intended tissues. The development of a new vector in gene therapy can improve the durability of a transgene expression. Also, the safety of the vector, if administered systemically, may resolve several problems, such as durability of expression and the host immune response. Currently, MSCs are prominent candidates as cell vehicles for both preclinical and clinical trials due to the secretion of therapeutic agents in several cancers. In the present study, we discuss the status of gene therapy in both viral and non-viral vectors along with their limitations. Throughout this study, the use of several nano-carriers for gene therapy is also investigated. Finally, we critically discuss the promising advantages of MSCs in targeted gene delivery, tumor inhibition and their utilization as the gene carriers in clinical situations.
Keywords: Gene therapy, mesenchymal stem cells, nano-carrier vectors, gene immunotherapies, bone marrow, cell therapy vehicles.
Graphical Abstract
[http://dx.doi.org/10.1021/mp200151a] [PMID: 21755953]
[http://dx.doi.org/10.1038/emm.2013.2]
[http://dx.doi.org/10.1007/s12306-008-0057-0] [PMID: 18791684]
[http://dx.doi.org/10.1634/stemcells.22-4-625] [PMID: 15277708]
[http://dx.doi.org/10.1002/jcb.20904] [PMID: 16795045]
[http://dx.doi.org/10.1016/j.exphem.2004.04.001] [PMID: 15246162]
[http://dx.doi.org/10.1089/scd.2007.0036] [PMID: 18047393]
[http://dx.doi.org/10.1002/jcp.26878] [PMID: 30144312]
[http://dx.doi.org/10.1038/mt.2012.93] [PMID: 22652996]
[http://dx.doi.org/10.1016/j.pharep.2018.05.008] [PMID: 30340096]
[http://dx.doi.org/10.1038/gt.2011.68] [PMID: 21562594]
[http://dx.doi.org/10.1038/mt.2009.41] [PMID: 19277019]
[http://dx.doi.org/10.1038/mt.2009.237] [PMID: 19844197]
[http://dx.doi.org/10.1126/science.286.5448.2244] [PMID: 10636774]
[http://dx.doi.org/10.1016/j.biomaterials.2009.06.051] [PMID: 19615741]
[http://dx.doi.org/10.1089/ten.a.2007.0102] [PMID: 18333806]
[http://dx.doi.org/10.1016/j.ijpharm.2004.07.035] [PMID: 15607268]
[http://dx.doi.org/10.1248/bpb.32.311] [PMID: 19182397]
[http://dx.doi.org/10.4103/0970-9290.35832] [PMID: 17938498]
[http://dx.doi.org/10.1038/sj.leu.2402085] [PMID: 11368355]
[http://dx.doi.org/10.1038/nrg1066] [PMID: 12728277]
[http://dx.doi.org/10.1186/s10020-018-0051-4] [PMID: 30249178]
[http://dx.doi.org/10.1038/nature15818] [PMID: 26469046]
[http://dx.doi.org/10.1038/ncomms2550] [PMID: 23462992]
[http://dx.doi.org/10.1038/ni.3002] [PMID: 25329189]
[http://dx.doi.org/10.1155/2017/8286248]
[http://dx.doi.org/10.1016/j.molmed.2011.10.004] [PMID: 22118960]
[http://dx.doi.org/10.1007/s11051-011-0423-y]
[http://dx.doi.org/10.1289/ehp.7339] [PMID: 16002369]
[http://dx.doi.org/10.1002/tox.21917] [PMID: 24753078]
[http://dx.doi.org/10.1186/1477-3155-10-31] [PMID: 22817658]
[http://dx.doi.org/10.1533/9780857097026.2.327]
[http://dx.doi.org/10.2174/1566523218666180119121949] [PMID: 29357792]
[http://dx.doi.org/10.1021/mp500656v] [PMID: 25531409]
[http://dx.doi.org/10.1038/sj.gt.3302720] [PMID: 16462855]
[http://dx.doi.org/10.1007/s00253-003-1321-8] [PMID: 12719940]
[http://dx.doi.org/10.2174/1877912304666140304000133]
[http://dx.doi.org/10.3390/s100807323] [PMID: 22163605]
[http://dx.doi.org/10.1259/bjr/59448833] [PMID: 22010024]
[http://dx.doi.org/10.1016/j.drudis.2015.05.009] [PMID: 26007605]
[http://dx.doi.org/10.1016/j.nantod.2015.06.008]
[http://dx.doi.org/10.1038/mt.2014.30] [PMID: 24599278]
[http://dx.doi.org/10.1016/j.tibtech.2016.12.009] [PMID: 28108036]
[http://dx.doi.org/10.1166/jbn.2014.1824] [PMID: 24804548]
[http://dx.doi.org/10.1088/0957-4484/17/13/021]
[http://dx.doi.org/10.1039/c3cc45834b] [PMID: 24026136]
[http://dx.doi.org/10.1039/C5OB00295H] [PMID: 25690723]
[http://dx.doi.org/10.1039/C5TB00614G] [PMID: 32262602]
[http://dx.doi.org/10.1007/s13233-019-7098-0]
[http://dx.doi.org/10.5281/zenodo.1110580]
[http://dx.doi.org/10.1039/C7QI00569E]
[http://dx.doi.org/10.1088/0957-4484/19/40/405102] [PMID: 21832609]
[http://dx.doi.org/10.4161/hv.26796] [PMID: 24128651]
[http://dx.doi.org/10.1002/smll.201001522] [PMID: 21360803]
[http://dx.doi.org/10.1039/C4CS00300D] [PMID: 25519856]
[http://dx.doi.org/10.1021/am5008134] [PMID: 24673573]
[http://dx.doi.org/10.1088/0022-3727/42/11/113001]
[http://dx.doi.org/10.3390/s111211736] [PMID: 22247690]
[http://dx.doi.org/10.3390/jfb2040355] [PMID: 24956449]
[http://dx.doi.org/10.1186/1556-276X-9-108] [PMID: 24597852]
[PMID: 25506215]
[http://dx.doi.org/10.1186/1556-276X-9-252] [PMID: 24936161]
[http://dx.doi.org/10.1016/j.ajps.2013.07.009]
[http://dx.doi.org/10.1016/j.ymthe.2004.12.006] [PMID: 15727930]
[http://dx.doi.org/10.2174/1381612053382133] [PMID: 15723632]
[http://dx.doi.org/10.1002/med.20090] [PMID: 17022036]
[http://dx.doi.org/10.1016/j.jconrel.2009.12.001] [PMID: 19969034]
[http://dx.doi.org/10.1073/pnas.84.21.7413] [PMID: 2823261]
[http://dx.doi.org/10.1016/S0014-5793(97)01532-9] [PMID: 9462842]
[http://dx.doi.org/10.1016/j.biomaterials.2009.11.003] [PMID: 19913908]
[http://dx.doi.org/10.1111/j.1439-0469.1987.tb00596.x]
[http://dx.doi.org/10.2217/nnm.13.192] [PMID: 24354813]
[http://dx.doi.org/10.1158/0008-5472.CAN-08-0127] [PMID: 18974128]
[http://dx.doi.org/10.1097/MJT.0b013e3181800591] [PMID: 19092639]
[http://dx.doi.org/10.1038/nm1391] [PMID: 16582917]
[http://dx.doi.org/10.1073/pnas.042678299] [PMID: 11854516]
[http://dx.doi.org/10.1016/j.orthres.2005.01.013] [PMID: 16140187]
[http://dx.doi.org/10.1016/j.yexcr.2004.11.011] [PMID: 15707576]
[http://dx.doi.org/10.1089/ten.2004.10.1093] [PMID: 15363167]
[http://dx.doi.org/10.1242/jcs.02932] [PMID: 16684817]
[http://dx.doi.org/10.1002/jgm.716]
[http://dx.doi.org/10.1038/sj.mt.6300022]
[http://dx.doi.org/10.4049/jimmunol.179.3.1855] [PMID: 17641052]
[http://dx.doi.org/10.1159/000047856] [PMID: 11340257]
[http://dx.doi.org/10.1089/scd.2008.0213] [PMID: 19049404]
[http://dx.doi.org/10.1073/pnas.0437997100] [PMID: 12606728]
[http://dx.doi.org/10.1172/JCI25540] [PMID: 16007248]
[http://dx.doi.org/10.1093/jnci/djh299] [PMID: 15523088]
[http://dx.doi.org/10.1371/journal.pone.0000416] [PMID: 17476338]
[http://dx.doi.org/10.1634/stemcells.2007-1104] [PMID: 18511601]
[http://dx.doi.org/10.1158/0008-5472.CAN-07-1406] [PMID: 18089798]
[http://dx.doi.org/10.1038/gt.2010.10] [PMID: 20220785]
[http://dx.doi.org/10.1016/j.mrrev.2008.03.002] [PMID: 18485806]
[http://dx.doi.org/10.1634/stemcells.2005-0260] [PMID: 16339642]
[http://dx.doi.org/10.1038/86439] [PMID: 11283651]
[http://dx.doi.org/10.1155/2012/217910]
[http://dx.doi.org/10.1371/journal.pone.0012920] [PMID: 20886110]
[http://dx.doi.org/10.1155/2018/3057624]
[http://dx.doi.org/10.1016/j.vetimm.2014.06.002] [PMID: 25026887]
[PMID: 31312397]
[http://dx.doi.org/10.1111/j.1600-065X.2009.00799.x] [PMID: 19594641]
[http://dx.doi.org/10.1182/blood-2005-07-2793] [PMID: 16293599]
[http://dx.doi.org/10.1016/j.stem.2009.05.003] [PMID: 19570514]
[http://dx.doi.org/10.1038/s41423-019-0204-6] [PMID: 30778166]
[http://dx.doi.org/10.1186/s13287-017-0742-8] [PMID: 29273086]
[http://dx.doi.org/10.1038/icb.2012.60] [PMID: 23146942]
[http://dx.doi.org/10.1038/nri2395] [PMID: 19172693]
[http://dx.doi.org/10.1182/blood.V99.10.3838] [PMID: 11986244]
[http://dx.doi.org/10.1073/pnas.0706832104] [PMID: 18042719]
[http://dx.doi.org/10.1073/pnas.1007967107] [PMID: 21135221]
[http://dx.doi.org/10.1161/CIRCULATIONAHA.112.000324]
[http://dx.doi.org/10.1016/j.jaut.2008.10.004] [PMID: 19062254]
[http://dx.doi.org/10.4049/jimmunol.0903143] [PMID: 20382885]
[http://dx.doi.org/10.1073/pnas.0910720107] [PMID: 20231466]
[http://dx.doi.org/10.3109/08820139.2011.619022] [PMID: 22017637]
[http://dx.doi.org/10.1186/1756-8722-5-19] [PMID: 22546280]
[http://dx.doi.org/10.1080/14653240310003611] [PMID: 14660044]
[http://dx.doi.org/10.1111/j.1399-0039.2006.00739.x] [PMID: 17212702]
[http://dx.doi.org/10.1182/blood-2007-02-074997] [PMID: 17951526]
[http://dx.doi.org/10.1016/j.intimp.2010.06.019] [PMID: 20619384]
[http://dx.doi.org/10.1186/1423-0127-16-30] [PMID: 19272130]
[http://dx.doi.org/10.1093/nar/20.6.1293] [PMID: 1313966]
[http://dx.doi.org/10.2174/1389450013348245] [PMID: 11732638]
[http://dx.doi.org/10.1016/0955-3886(95)00055-0] [PMID: 10163393]
[http://dx.doi.org/10.1089/hum.1997.8.12-1417] [PMID: 9287142]
[http://dx.doi.org/10.1038/sj.bmt.1702791] [PMID: 11277170]
[http://dx.doi.org/10.1038/74447] [PMID: 10748519]
[http://dx.doi.org/10.1152/ajpgi.00415.2001] [PMID: 12181193]
[http://dx.doi.org/10.1634/stemcells.2006-0286] [PMID: 17053211]
[http://dx.doi.org/10.3109/08916930903305641] [PMID: 19845478]
[http://dx.doi.org/10.1016/j.cytogfr.2009.10.002] [PMID: 19926330]
[http://dx.doi.org/10.1084/jem.20051921] [PMID: 16636132]
[PMID: 12097260]
[http://dx.doi.org/10.1016/j.jhep.2004.08.015] [PMID: 15582131]
[http://dx.doi.org/10.1158/0008-5472.CAN-04-1874] [PMID: 15833864]
[http://dx.doi.org/10.1158/1535-7163.MCT-05-0334] [PMID: 16546991]
[http://dx.doi.org/10.1007/s10549-006-9449-8] [PMID: 17221158]
[http://dx.doi.org/10.1158/1078-0432.CCR-07-0133] [PMID: 17699866]
[http://dx.doi.org/10.1111/j.1365-2710.2007.00800.x] [PMID: 17286784]
[http://dx.doi.org/10.1158/1541-7786.MCR-06-0002] [PMID: 16513837]
[PMID: 12235011]
[http://dx.doi.org/10.1096/fj.04-2863rev] [PMID: 15746176]
[http://dx.doi.org/10.1038/35094059] [PMID: 11900251]
[http://dx.doi.org/10.1002/stem.81] [PMID: 19544460]
[http://dx.doi.org/10.1002/stem.613] [PMID: 21308868]
[http://dx.doi.org/10.1007/s00395-011-0168-x] [PMID: 21424917]
[PMID: 21712019]
[http://dx.doi.org/10.1172/JCI31377] [PMID: 17948129]
[http://dx.doi.org/10.1016/j.ccr.2007.02.027] [PMID: 17482132]
[http://dx.doi.org/10.1016/j.ccr.2011.01.020] [PMID: 21316604]
[http://dx.doi.org/10.1126/science.1099513] [PMID: 15567866]
[http://dx.doi.org/10.1158/0008-5472.CAN-08-0943] [PMID: 18519693]
[http://dx.doi.org/10.1158/0008-5472.CAN-06-4690] [PMID: 17909019]
[http://dx.doi.org/10.1158/0008-5472.CAN-08-4630] [PMID: 19509230]
[http://dx.doi.org/10.2741/2808] [PMID: 17981676]
[http://dx.doi.org/10.1634/stemcells.21-4-389] [PMID: 12832693]
[http://dx.doi.org/10.1038/nature06188] [PMID: 17914389]
[http://dx.doi.org/10.1073/pnas.0900244106] [PMID: 19234121]
[http://dx.doi.org/10.4161/cbt.7.2.5296] [PMID: 18059192]
[http://dx.doi.org/10.3390/ijms161226215] [PMID: 26694366]
[http://dx.doi.org/10.3390/cancers10070222] [PMID: 29970850]
[http://dx.doi.org/10.1155/2014/109389]
[http://dx.doi.org/10.1080/14653240902807026] [PMID: 19308770]
[http://dx.doi.org/10.1038/cr.2008.40] [PMID: 18364678]
[http://dx.doi.org/10.1182/blood-2008-09-176198] [PMID: 19036701]
[http://dx.doi.org/10.1073/pnas.1615396113] [PMID: 27849590]
[http://dx.doi.org/10.1002/stem.1903] [PMID: 25420617]
[http://dx.doi.org/10.1152/ajplung.00353.2001] [PMID: 11880304]
[http://dx.doi.org/10.1159/000080341] [PMID: 15319535]
[http://dx.doi.org/10.1016/j.exphem.2005.07.003] [PMID: 16263424]
[http://dx.doi.org/10.1016/S1471-4906(02)02302-5] [PMID: 12401408]
[http://dx.doi.org/10.1016/S1567-5769(02)00064-4] [PMID: 12349942]
[http://dx.doi.org/10.1189/jlb.0609385] [PMID: 19741157]
[http://dx.doi.org/10.1111/j.1600-065X.2008.00607.x] [PMID: 18364000]
[http://dx.doi.org/10.1634/stemcells.2007-0563] [PMID: 17916800]
[http://dx.doi.org/10.1371/journal.pone.0045590] [PMID: 23029122]
[http://dx.doi.org/10.1186/1471-2407-10-665] [PMID: 21129170]
[http://dx.doi.org/10.1016/j.cell.2014.05.010] [PMID: 24906146]
[http://dx.doi.org/10.1038/srep19648] [PMID: 26782778]
[http://dx.doi.org/10.1016/j.stem.2016.07.001] [PMID: 27524438]
[http://dx.doi.org/10.1016/j.tibtech.2015.12.014] [PMID: 26809780]
[http://dx.doi.org/10.1038/gt.2016.28] [PMID: 27052801]
[http://dx.doi.org/10.1186/s13287-017-0511-8] [PMID: 28279194]