Abstract
Exosomes secreted by mesenchymal stem/stromal cells (MSC-Exos) are advantageous candidate sources for novel acellular therapy. Despite the current standards of good manufacturing practice (GMP), the deficiency of suitable quality-control methods and the difficulties in large-scale preparation largely restrict the development of therapeutic products and their clinical applications worldwide. Herein, we mainly focus on three dominating issues commonly encountered in exosomal GMP, including issues upstream of the cell culture process, downstream of the purification process, exosomes quality control, and the drug properties of exosomes and their druggability from a corporate perspective. Collectively, in this review article, we put forward the issues of preparing clinical exosome drugs for the treatment of diverse diseases and provide new references for the clinical application of GMP-grade MSC-Exos.
Keywords: Exosomes, druggability, quality control, autocrine, sucrose, clinical application.
[http://dx.doi.org/10.2174/1381612811319130015] [PMID: 23278600]
[http://dx.doi.org/10.1186/s13287-015-0122-1] [PMID: 26206376]
[http://dx.doi.org/10.1038/nm0405-367] [PMID: 15812508]
[http://dx.doi.org/10.7150/thno.54004] [PMID: 33754070]
[http://dx.doi.org/10.1016/j.biocel.2011.10.005] [PMID: 22024155]
[http://dx.doi.org/10.1002/sctm.17-0055] [PMID: 28714557]
[http://dx.doi.org/10.7150/thno.33872] [PMID: 31534531]
[http://dx.doi.org/10.1016/j.bbadis.2014.10.008] [PMID: 25463630]
[http://dx.doi.org/10.1016/j.jaci.2012.12.1565] [PMID: 23414598]
[http://dx.doi.org/10.1016/j.biomaterials.2019.02.006] [PMID: 30771585]
[http://dx.doi.org/10.1038/emm.2017.63] [PMID: 28620221]
[http://dx.doi.org/10.1007/5584_2018_219] [PMID: 29774506]
[http://dx.doi.org/10.1089/scd.2020.0080] [PMID: 32380908]
[http://dx.doi.org/10.3389/fendo.2023.1205901] [PMID: 37564988]
[http://dx.doi.org/10.3390/cells9051157] [PMID: 32392899]
[http://dx.doi.org/10.1371/journal.pbio.3000599]
[http://dx.doi.org/10.3402/jev.v4.30087] [PMID: 26725829]
[http://dx.doi.org/10.1016/j.jconrel.2019.07.021] [PMID: 31325471]
[http://dx.doi.org/10.1016/j.ymeth.2015.02.019] [PMID: 25766927]
[http://dx.doi.org/10.1016/j.molmed.2018.01.006] [PMID: 29449149]
[http://dx.doi.org/10.1016/j.biotechadv.2018.09.001] [PMID: 30218694]
[http://dx.doi.org/10.1164/rccm.200902-0242OC] [PMID: 19713447]
[http://dx.doi.org/10.3171/2014.11.JNS14770] [PMID: 25594326]
[http://dx.doi.org/10.1016/j.scr.2009.12.003] [PMID: 20138817]
[http://dx.doi.org/10.3892/etm.2016.3076] [PMID: 27073476]
[http://dx.doi.org/10.3389/fcvm.2017.00063] [PMID: 29062835]
[http://dx.doi.org/10.1164/rccm.201705-0925OC] [PMID: 28853608]
[http://dx.doi.org/10.1161/CIRCULATIONAHA.112.114173] [PMID: 23114789]
[http://dx.doi.org/10.1093/cvr/cvw054] [PMID: 26980205]
[http://dx.doi.org/10.1038/ncomms9472] [PMID: 26442449]
[http://dx.doi.org/10.1016/j.ijcard.2014.12.043] [PMID: 25590961]
[http://dx.doi.org/10.1159/000438594] [PMID: 26646808]
[http://dx.doi.org/10.1111/neup.12020] [PMID: 23384285]
[http://dx.doi.org/10.1038/srep34562] [PMID: 27686625]
[http://dx.doi.org/10.1002/sctm.16-0428] [PMID: 28198592]
[http://dx.doi.org/10.1038/jcbfm.2013.152] [PMID: 23963371]
[http://dx.doi.org/10.1016/B978-0-444-63486-3.00001-3] [PMID: 25410351]
[http://dx.doi.org/10.1089/scd.2012.0395] [PMID: 23002959]
[http://dx.doi.org/10.1186/s12967-015-0417-0] [PMID: 25638205]
[http://dx.doi.org/10.1095/biolreprod.111.095760] [PMID: 22133690]
[http://dx.doi.org/10.7150/ijbs.10725] [PMID: 25632267]
[http://dx.doi.org/10.1155/2012/971907] [PMID: 22852084]
[http://dx.doi.org/10.1182/blood-2007-03-078709] [PMID: 17536014]
[http://dx.doi.org/10.3389/fncel.2014.00377] [PMID: 25426026]
[http://dx.doi.org/10.3389/fnmol.2014.00011] [PMID: 24574964]
[http://dx.doi.org/10.1038/srep01197] [PMID: 23378928]
[http://dx.doi.org/10.1089/scd.2013.0479] [PMID: 24367916]
[http://dx.doi.org/10.1016/j.intimp.2023.110566] [PMID: 37418985]
[http://dx.doi.org/10.1038/srep13721] [PMID: 26348153]
[http://dx.doi.org/10.1002/stem.1409] [PMID: 23630198]
[http://dx.doi.org/10.1172/JCI63539] [PMID: 22820288]
[http://dx.doi.org/10.3892/ijmm.2012.1200] [PMID: 23229021]
[http://dx.doi.org/10.1089/scd.2018.0200] [PMID: 30638129]
[http://dx.doi.org/10.1111/jcmm.14228] [PMID: 31025509]
[http://dx.doi.org/10.7150/thno.37357] [PMID: 31660076]
[http://dx.doi.org/10.3390/genes12122015] [PMID: 34946963]
[http://dx.doi.org/10.1002/cam4.3263] [PMID: 32627968]
[http://dx.doi.org/10.3390/cancers13061373] [PMID: 33803617]
[http://dx.doi.org/10.1016/j.msec.2019.01.122] [PMID: 30889706]
[http://dx.doi.org/10.7150/thno.29579] [PMID: 31037144]
[http://dx.doi.org/10.21037/tau-20-421] [PMID: 33968679]
[http://dx.doi.org/10.1186/s13287-020-01937-8] [PMID: 32993783]
[http://dx.doi.org/10.1371/journal.pone.0042840] [PMID: 22912749]
[http://dx.doi.org/10.18632/oncotarget.2530] [PMID: 25296979]
[http://dx.doi.org/10.1016/j.exer.2016.06.022] [PMID: 27381329]
[http://dx.doi.org/10.1089/ten.tea.2011.0325] [PMID: 22443121]
[http://dx.doi.org/10.18632/aging.103010] [PMID: 32259794]
[http://dx.doi.org/10.1007/s12015-020-10014-9] [PMID: 32772239]
[PMID: 35087716]
[http://dx.doi.org/10.1038/s41591-023-02632-w] [PMID: 37919438]
[http://dx.doi.org/10.3402/jev.v2i0.20360] [PMID: 24009894]
[http://dx.doi.org/10.3402/jev.v4.29260] [PMID: 26563735]
[http://dx.doi.org/10.1038/nmeth.4185] [PMID: 28245209]
[http://dx.doi.org/10.3402/jev.v3.24783] [PMID: 25317276]
[http://dx.doi.org/10.1016/j.jcyt.2017.01.001] [PMID: 28188071]
[http://dx.doi.org/10.1016/S0022-1759(02)00330-7] [PMID: 12379326]
[http://dx.doi.org/10.3389/fphys.2018.01169] [PMID: 30197601]
[http://dx.doi.org/10.1172/jci.insight.99263] [PMID: 29669940]
[http://dx.doi.org/10.1089/ten.tea.2011.0690] [PMID: 22578283]
[http://dx.doi.org/10.1186/scrt234] [PMID: 23856418]
[http://dx.doi.org/10.1002/adfm.201909125] [PMID: 32952493]
[http://dx.doi.org/10.1002/cbin.10097] [PMID: 23505143]
[http://dx.doi.org/10.1042/CS20120226] [PMID: 22876972]
[http://dx.doi.org/10.5966/sctm.2015-0191] [PMID: 27102647]
[http://dx.doi.org/10.1002/stem.2298] [PMID: 26782178]
[PMID: 29141446]
[http://dx.doi.org/10.1016/j.yexcr.2019.111541] [PMID: 31369752]
[http://dx.doi.org/10.1073/pnas.1008117107] [PMID: 20643923]
[http://dx.doi.org/10.1016/j.actbio.2017.12.025] [PMID: 29281806]
[http://dx.doi.org/10.1016/j.reth.2024.01.009] [PMID: 38374989]
[http://dx.doi.org/10.1038/aps.2017.12] [PMID: 28392567]
[http://dx.doi.org/10.1080/20013078.2018.1535750] [PMID: 30637094]
[http://dx.doi.org/10.3390/ijms17010013] [PMID: 26712742]
[http://dx.doi.org/10.7150/thno.18133] [PMID: 28255367]
[http://dx.doi.org/10.1371/journal.pone.0096094] [PMID: 24816817]
[http://dx.doi.org/10.1038/s41556-018-0250-9] [PMID: 30602770]
[http://dx.doi.org/10.1016/j.ymeth.2015.05.028] [PMID: 26044649]
[http://dx.doi.org/10.1002/0471143030.cb0322s30] [PMID: 18228490]
[http://dx.doi.org/10.1016/0006-3002(60)90228-6] [PMID: 13792408]
[http://dx.doi.org/10.1101/pdb.top074476] [PMID: 25834266]
[http://dx.doi.org/10.1371/journal.pone.0199438] [PMID: 29933408]
[http://dx.doi.org/10.1039/D1AN00373A] [PMID: 34105528]
[http://dx.doi.org/10.1016/j.pep.2018.05.007] [PMID: 29777748]
[http://dx.doi.org/10.1021/ef700410e]
[http://dx.doi.org/10.1172/jci.insight.89631] [PMID: 27882350]
[http://dx.doi.org/10.1111/jth.13190] [PMID: 26564379]
[http://dx.doi.org/10.1007/978-1-4939-7253-1_24] [PMID: 28828666]
[http://dx.doi.org/10.1021/acs.jproteome.7b00770] [PMID: 29397740]
[http://dx.doi.org/10.1681/ASN.2015090994] [PMID: 26940098]
[http://dx.doi.org/10.1007/s00018-018-2773-4] [PMID: 29441425]
[http://dx.doi.org/10.1038/nature05058] [PMID: 16871203]
[http://dx.doi.org/10.1016/j.bcmd.2005.06.008] [PMID: 16061407]
[http://dx.doi.org/10.1016/j.xphs.2019.05.027] [PMID: 31150697]
[http://dx.doi.org/10.3390/bioengineering6030075] [PMID: 31466238]
[http://dx.doi.org/10.1111/jth.12602] [PMID: 24818656]
[http://dx.doi.org/10.1016/j.xphs.2016.08.009] [PMID: 27663383]
[http://dx.doi.org/10.1007/978-1-4939-7253-1_13] [PMID: 28828655]
[http://dx.doi.org/10.1002/anie.201603007] [PMID: 27457402]
[http://dx.doi.org/10.1016/j.bbamcr.2018.09.008] [PMID: 30290236]
[http://dx.doi.org/10.1373/clinchem.2018.291963] [PMID: 30021922]
[http://dx.doi.org/10.1080/20013078.2019.1587567] [PMID: 30949308]
[http://dx.doi.org/10.1039/C4LC00662C] [PMID: 25099143]
[http://dx.doi.org/10.1186/s13046-019-1095-1] [PMID: 30770776]
[http://dx.doi.org/10.2217/nnm-2016-0097] [PMID: 27480794]
[http://dx.doi.org/10.1016/bs.mie.2020.06.011] [PMID: 33565970]
[http://dx.doi.org/10.1371/journal.pone.0231994] [PMID: 33497388]
[http://dx.doi.org/10.1016/bs.mie.2020.05.013] [PMID: 33565978]
[http://dx.doi.org/10.1021/cc0501413] [PMID: 16676994]
[http://dx.doi.org/10.1111/j.1600-0854.2009.00920.x] [PMID: 19490536]
[http://dx.doi.org/10.1093/hmg/dds317] [PMID: 22872698]
[http://dx.doi.org/10.1155/2019/5214821] [PMID: 30800670]
[http://dx.doi.org/10.1080/20013078.2018.1442088] [PMID: 29535850]
[http://dx.doi.org/10.1073/pnas.1521230113] [PMID: 26858453]
[http://dx.doi.org/10.3402/jev.v5.29828] [PMID: 26928672]
[http://dx.doi.org/10.1002/wnan.1395] [PMID: 26888041]
[http://dx.doi.org/10.1002/bit.20596] [PMID: 16037986]
[http://dx.doi.org/10.1016/j.omtm.2018.12.003] [PMID: 30719485]
[http://dx.doi.org/10.3389/fimmu.2014.00556] [PMID: 25414703]
[http://dx.doi.org/10.1089/scd.2014.0563] [PMID: 25779336]
[http://dx.doi.org/10.1073/pnas.0914843107] [PMID: 20304794]
[http://dx.doi.org/10.1074/jbc.M110.107821] [PMID: 20353945]
[http://dx.doi.org/10.1186/s13287-015-0214-y] [PMID: 26560482]
[http://dx.doi.org/10.18632/oncotarget.16778] [PMID: 28423355]
[http://dx.doi.org/10.1007/s13402-017-0335-7] [PMID: 28741069]
[http://dx.doi.org/10.1002/stem.2564] [PMID: 28090688]
[http://dx.doi.org/10.1111/jcmm.13170] [PMID: 28382720]
[http://dx.doi.org/10.1111/jcmm.13208] [PMID: 28544786]
[http://dx.doi.org/10.5966/sctm.2015-0367] [PMID: 27388239]
[http://dx.doi.org/10.1016/j.stem.2014.01.013] [PMID: 24506881]