Unlocking the promise of mRNA therapeutics

Nature Biotechnology, Journal Year: 2022, Volume and Issue: 40(11), P. 1586 - 1600

Published: Nov. 1, 2022

Language: Английский

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Mesenchymal stem cell-derived exosomes in cancer therapy resistance: recent advances and therapeutic potential

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: Sept. 13, 2022

Abstract Mesenchymal stem cells (MSCs) are multipotent stromal that can be obtained from various human tissues and organs. They differentiate into a wide range of cell types, including osteoblasts, adipocytes chondrocytes, thus exhibiting great potential in regenerative medicine. Numerous studies have indicated MSCs play critical roles cancer biology. The crosstalk between tumour has been found to regulate many behaviours, such as proliferation, metastasis epithelial-mesenchymal transition (EMT). Multiple lines evidence demonstrated secrete exosomes modulate the microenvironment important development. Notably, very recent works shown mesenchymal cell-derived (MSC-derived exosomes) critically involved resistance chemotherapy agents, targeted-therapy drugs, radiotherapy immunotherapy. In this review, we systematically summarized emerging detailed molecular mechanisms MSC-derived mediating therapy resistance, providing novel insights clinical applications management.

Language: Английский

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Hybrid exosomes, exosome-like nanovesicles and engineered exosomes for therapeutic applications

Journal of Controlled Release, Journal Year: 2022, Volume and Issue: 353, P. 1127 - 1149

Published: Dec. 26, 2022

Language: Английский

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Plant-derived extracellular vesicles: a novel nanomedicine approach with advantages and challenges

Cell Communication and Signaling, Journal Year: 2022, Volume and Issue: 20(1)

Published: May 23, 2022

Abstract Background Many eukaryote cells produce membrane-enclosed extracellular vesicles (EVs) to establish cell-to-cell communication. Plant-derived EVs (P-EVs) contain proteins, RNAs, lipids, and other metabolites that can be isolated from the juice, flesh, roots of many species. Methods In present review study, we studied numerous articles over past two decades published on role P-EVs in plant physiology as well application these different diseases. Results Different types have been identified plants multiple functions including reorganization cell structure, development, facilitating crosstalk between fungi, immunity, defense against pathogens. Purified several edible species, are more biocompatible, biodegradable, extremely available plants, making them useful for cell-free therapy. Emerging evidence clinical preclinical studies suggest benefits conventional synthetic carriers, opening novel frontiers drug-delivery system. Exciting new opportunities, designing drug-loaded improve systems, already being examined, however translation P-EVs-based therapies faces challenges. Conclusion hold great promise treatment addition, despite enthusiastic results, further scrutiny should focus unravelling detailed mechanism behind biogenesis trafficking their therapeutic applications.

Language: Английский

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Exosomes and cancer - Diagnostic and prognostic biomarkers and therapeutic vehicle

Oncogenesis, Journal Year: 2022, Volume and Issue: 11(1)

Published: Sept. 15, 2022

Abstract Exosomes belong to a subpopulation of extracellular vesicles secreted by the dynamic multistep endocytosis process and carry diverse functional molecular cargoes, including proteins, lipids, nucleic acids (DNA, messenger noncoding RNA), metabolites promote intercellular communication. Proteins RNA are among most abundant contents in exosomes; they have biological functions selectively packaged into exosomes. derived from tumor, stromal immune cells contribute multiple stages cancer progression as well resistance therapy. In this review, we will discuss biogenesis exosomes their roles development. Since specific within originate origin, property allows function valuable biomarkers. We also potential use diagnostic prognostic biomarkers or predictors for different therapeutic strategies cancers. Furthermore, applications direct targets engineered vehicles drugs an important field exosome study. Better understanding biology may pave way promising exosome-based clinical applications.

Language: Английский

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Macrophage Cell Membrane‐Cloaked Nanoplatforms for Biomedical Applications

Small Methods, Journal Year: 2022, Volume and Issue: 6(8)

Published: June 29, 2022

Abstract Biomimetic approaches utilize natural cell membrane‐derived nanovesicles to camouflage nanoparticles circumvent some limitations of nanoscale materials. This emergent membrane‐coating technology is inspired by naturally occurring intercellular interactions, efficiently guide nanostructures the desired locations, thereby increasing both therapeutic efficacy and safety. In addition, intrinsic biocompatibility membranes allows crossing biological barriers avoids elimination immune system. results in enhanced blood circulation time lower toxicity vivo. Macrophages are major phagocytic cells innate They equipped with a complex repertoire surface receptors, enabling them respond signals, exhibit tropism inflammatory sites tumorous tissues. Macrophage membrane‐functionalized nanosystems designed combine advantages macrophages nanomaterials, improving ability those reach target sites. Recent studies have demonstrated potential these biomimetic for targeted delivery drugs imaging agents tumors, inflammatory, infected The present review covers preparation biomedical applications macrophage membrane‐coated nanosystems. Challenges future perspectives development addressed.

Language: Английский

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Natural and synthetic nanovectors for cancer therapy

Nanotheranostics, Journal Year: 2023, Volume and Issue: 7(3), P. 236 - 257

Published: Jan. 1, 2023

Nanomaterials have been extensively studied in cancer therapy as vectors that may improve drug delivery.Such not only bring numerous advantages such stability, biocompatibility, and cellular uptake but also shown to overcome some cancer-related resistances.Nanocarrier can deliver the more precisely specific organ while improving its pharmacokinetics, thereby avoiding secondary adverse effects on target tissue.Between these nanovectors, diverse material types be discerned, liposomes, dendrimers, carbon nanostructures, nanoparticles, nanowires, etc., each of which offers different opportunities for therapy.In this review, a broad spectrum nanovectors is analyzed application multimodal diagnostics terms mode action pharmacokinetics.Advantages inconveniences promising including gold SPIONs, semiconducting quantum dots, various phospholipid-based polymeric micelles, extracellular exome vesicles are summarized.The article concluded with future outlook field.

Language: Английский

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Exosomes as bio-inspired nanocarriers for RNA delivery: preparation and applications

Journal of Translational Medicine, Journal Year: 2022, Volume and Issue: 20(1)

Published: March 14, 2022

Abstract Nanocarriers as drug/biomolecule delivery systems have been significantly developed during recent decades. Given the stability, reasonable efficiency, and safety of nanocarriers, there are several barriers in fulfillment successful clinical application these systems. These challenges encouraged drug researchers to establish innovative nanocarriers with longer circulation time, high compatibility. Exosomes extracellular nanometer-sized vesicles released through various cells. serve possessing great potential overcome some obstacles encountered gene due their natural affinity recipient cells inherent capability shuttle genes, lipids, proteins, RNAs between So far, has a lot valuable research on by exosomes, but RNA delivery, especially mRNA, is very limited. Since mRNA-based vaccines therapies recently gained particular prominence diseases, it essential find suitable system large size destructive nature nucleic acids. That's why we're going take look at unique features exosomes isolation loading methods, embrace this idea that exosome-mediated would be introduced efficient strategy disease treatment within near future. Graphical

Language: Английский

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Extracellular vesicles: The next generation in gene therapy delivery

Molecular Therapy, Journal Year: 2023, Volume and Issue: 31(5), P. 1225 - 1230

Published: Jan. 25, 2023

Extracellular vesicles (EVs) are esteemed as a promising delivery vehicle for various genetic therapeutics. They relatively inert, non-immunogenic, biodegradable, and biocompatible. At least in rodents, they can even transit challenging bodily hurdles such the blood-brain barrier. Constitutively shed by all cells with potential to interact specifically neighboring distant targets, EVs be engineered carry deliver therapeutic molecules proteins RNAs. thus emerging an elegant vivo gene therapy vector. Deeper understanding of basic EV biology—including cellular production, loading, systemic distribution, cell delivery—is still needed effective harnessing these endogenous nanoparticles next-generation nanodelivery tools. However, perfect product will produce at clinical scale. In this regard, we propose that vector transduction technologies used convert either ex or directly into factories stable, safe modulation expression function. Here, extrapolate from current state art bright future using treat diseases refractory All eukaryotic release abundance extracellular (EVs): membrane-bound roughly spherical range diameter around 50 500 nm.1Wang W. Li M. Chen Z. Xu L. Chang Wang K. Deng C. Gu Y. Zhou S. Shen et al.Biogenesis function pathophysiological processes skeletal muscle atrophy.Biochem. Pharmacol. 2022; 198: 114954https://doi.org/10.1016/j.bcp.2022.114954Crossref Scopus (15) Google Scholar diverse, categorized not only size but also origin, mode release, molecular composition, Classical subtypes like "ectosomes" (plasma membrane origin) "exosomes" (endosomal may important biology level belie incredible diversity difficult distinguish after leave cell.2Buzas E.I. The roles immune system.Nat. Rev. Immunol. : 1-15https://doi.org/10.1038/s41577-022-00763-8Crossref (23) thought cell-to-cell communications delivering nucleic acids, proteins, small molecules, lipids between cells,3Li S.P. Lin Z.X. Jiang X.Y. Yu Exosomal cargo-loading synthetic exosome-mimics tools.Acta Sin. 2018; 39: 542-551https://doi.org/10.1038/aps.2017.178Crossref PubMed (182) other modes interaction envisioned. Notably, have been observed retain their recipient following being transported EVs, suggesting containing active RNAs, DNAs alter producer cells. These characteristics confer unparalleled terms safety biocompatibility; such, subject extensive experimentation captured interest both public private sectors.4Yang Wu S.Y. advances challenges utilizing exosomes cancer therapeutics.Front. 9: 735https://doi.org/10.3389/fphar.2018.00735Crossref (28) To date, several biomolecules repeatedly loaded delivered target experimentally validated vitro models. RNA therapeutics offer distinct advantages over zinc finger CRISPR therapeutics, RNAs pathways transient manner programmable easy engineer specific diseases, generally immunogenic, is unfortunately case many recombinant protein technologies. Various biotypes biological functions potential, interfering (siRNAs), discovered investigated, leading development new classes drugs.5Damase T.R. Sukhovershin R. Boada Taraballi F. Pettigrew R.I. Cooke J.P. limitless Bioeng. Biotechnol. 2021; 628137https://doi.org/10.3389/fbioe.2021.628137Crossref (136) impart short-term longer-term epigenetic silencing, which based on target, e.g., targeting promoters induce transcriptional silencing.6Weinberg M.S. Morris K.V. Transcriptional silencing humans.Nucleic Acids Res. 2016; 44: 6505-6517https://doi.org/10.1093/nar/gkw139Crossref (61) mRNA-based vaccines now effectively combat COVID-19 pandemic.7Kiaie S.H. Majidi Zolbanin N. Ahmadi A. Bagherifar Valizadeh H. Kashanchi Jafari Recent mRNA-LNP therapeutics: immunological pharmacological aspects.J. Nanobiotechnology. 20: 276https://doi.org/10.1186/s12951-022-01478-7Crossref (3) although rapidly altered produced, must reach intended effective. For example, lipid (LNPs) Pfizer-BioNTech vaccine treatment polyneuropathy targeted liver, approaches cytotoxic, unstable circulation, unsuited tissues.8Hou X. Zaks T. Langer Dong Lipid mRNA delivery.Nat. Mater. 6: 1078-1094https://doi.org/10.1038/s41578-021-00358-0Crossref (455) Moreover, subcellular RNA-based drugs formidable challenge, less than 1% payloads reaching cytosol cell.9Maugeri Nawaz Papadimitriou Angerfors Camponeschi Na Hölttä Skantze P. Johansson Sundqvist al.Linkage endosomal escape LNP-mRNA loading transport cells.Nat. Commun. 2019; 10: 4333https://doi.org/10.1038/s41467-019-12275-6Crossref (123) Potentially, packaging naturally RNA, could safer more physiologically approach. As attempts made integrate species optimize efficiency. While system, it has proven load cargo EVs. during biogenesis isolation physical chemical methods. Electroporation acids EVs; however, deteriorates intrinsic properties causes loss.10Johnsen K.B. Gudbergsson J.M. Skov M.N. Christiansen G. Gurevich Moos Duroux Evaluation electroporation-induced adverse effects adipose-derived stem exosomes.Cytotechnology. 68: 2125-2138https://doi.org/10.1007/s10616-016-9952-7Crossref (94) most common method transfect EV-producer plasmids encoding mRNA. resulting high concentration cytoplasmic sufficient cause perhaps because found functionally export components vast surplus.11Shrivastava multifunctionality exosomes; garbage bin next generation therapy.Genes (Basel). 12: 173https://doi.org/10.3390/genes12020173Crossref (4) Villamizar al. transfected mesenchymal (MSCs) plasmid transcription factor CFTR promoter cystic fibrosis (called CFZF). CFZF, plasmid's CMV promoter, was detect CFZF isolated EVs.12Villamizar O. Waters S.A. Scott Grepo Jaffe Mesenchymal Stem Cell exosome Zinc Finger Protein activation transmembrane conductance regulator.J. Extracell. Vesicles. e12053https://doi.org/10.1002/jev2.12053Crossref (13) increase output, Kojima catalase system called EXOtic,13Kojima Bojar D. Rizzi Hamri G.C.E. El-Baba M.D. Saxena Ausländer Tan K.R. Fussenegger Designer produced implanted intracerebrally Parkinson's disease treatment.Nat. 1305https://doi.org/10.1038/s41467-018-03733-8Crossref (297) consisting construct CD63, protein, plus L7Ae archaeal ribosomal selectively binds C/D box structure. Next, introduced 3′ UTR gene. When were constructs, efficiently packed transferred vitro.13Kojima A tricistronic three genes involved (STEAP3, SDC4, L-aspartate oxidase) EXOtic release. Introduced mouse models disease, transgressed barrier reduced reactive oxygen brain. constitutively mutant gap junction Connexin 43 (Cx43) included. This responsible forming gap-junction structures fusion two connexon hemichannels, allowing intercommunication transfer materials.14Soares A.R. Martins-Marques Ribeiro-Rodrigues Ferreira J.V. Catarino Pinho M.J. Zuzarte Isabel Anjo Manadas B. P G Sluijter J. al.Gap junctional Cx43 communication mammalian cells.Sci. Rep. 2015; 5: 13243https://doi.org/10.1038/srep13243Crossref (119) It expressed Cx present hexamers organized hemichannel structures.14Soares Scholar,15Gemel Kilkus Dawson Beyer E.C. Connecting connexins.Cancers 11: 476https://doi.org/10.3390/cancers11040476Crossref efficiency upon contact.12Villamizar Scholar,16Shrivastava Ray R.M. Holguin Echavarria T.A. Burnett Exosome-mediated stable repression HIV-1.Nat. 5541https://doi.org/10.1038/s41467-021-25839-2Crossref (16) Indeed, CD63-fused appears require co-transfection booster plasmid, Cx43, LAMP2b-fused brain module nluc-C/D Another generate lipid-coated particles purified through mixing-induced partitioning.17Sato Y.T. Umezaki Sawada Mukai Sasaki Harada Shiku Akiyoshi Engineering hybrid liposomes.Sci. 21933https://doi.org/10.1038/srep21933Crossref (333) Scholar,18Li Y.J. J.Y. Liu Qiu Huang Hu X.B. Xiang D.X. Artificial translational nanomedicine.J. 19: 242https://doi.org/10.1186/s12951-021-00986-2Crossref (62) expected, process leads slight decrease numbers, efficient accurate (>90%).19Tsai S.J. Atai N.A. Cacciottolo Nice Salehi Guo Sedgwick Kanagavelu Gould SARS-CoV-2 immunity.J. Biol. Chem. 297: 101266https://doi.org/10.1016/j.jbc.2021.101266Abstract Full Text PDF purification need pre-coat introduces expense time constraints. Therefore, while research purposes, prove scale commercial applications. MicroRNAs (miRNAs) well known modulate types.20Simeoli Montague Jones H.R. Castaldi Chambers Kelleher J.H. Vacca V. Pitcher Grist Al-Ahdal al.Exosomal including microRNA regulates sensory neuron macrophage nerve trauma.Nat. 2017; 8: 1778https://doi.org/10.1038/s41467-017-01841-5Crossref (155) direct interactions Argonaut 2 (AGO2), packaged EVs.21Beltrami Clayton Newbury L.J. Corish Jenkins R.H. Phillips A.O. Fraser D.J. Bowen Stabilization urinary association argonaute protein.Noncoding. RNA. 1: 151-166https://doi.org/10.3390/ncrna1020151Crossref (35) Alternatively, particular YBX1, implicated miRNAs EVs,22Liu X.M. Ma Schekman Selective sorting microRNAs phase-separated YBX1 condensates.Elife. e71982https://doi.org/10.7554/eLife.71982Crossref others suggested there motif pathway miRNA recruitment EVs.23Hung M.E. Leonard J.N. platform actively elucidate limiting steps EV-mediated delivery.J. 31027https://doi.org/10.3402/jev.v5.31027Crossref (112) Yet does appear EVs.24Albanese Y.F.A. Hüls Gärtner Tagawa Mejias-Perez E. Keppler O.T. Göbel Zeidler Shein al.MicroRNAs minor constituents rarely cells.PLoS Genet. 17: e1009951https://doi.org/10.1371/journal.pgen.1009951Crossref (40) Due large genes, significantly phenotype cell, therefore high-value promote, trigger, diseases. Simeoli among first describe neurons macrophages presence capsaicin.20Simeoli Capsaicin incubation injury miRNA-21 milk fat globule-EGF 8 MFG-E8, uptake. authors demonstrated derived capsaicin-treated taken up readily untreated control promoted inflammatory 13Kojima Scholarphenotypes miR-21 macrophages. Activated likely move toward sites where EV-releasing situated, demonstrating existence importance intercellular mediated miRNAs.20Simeoli EV-transferred promoting metastasis, drug resistance, proliferation, inflammation.25Dilsiz Role exosomal cancer.Future Sci. OA. 2020; FSO465https://doi.org/10.2144/fsoa-2019-0116Crossref (60) EV-loaded pathways, seem preferentially relative types, exists within AGO2 RNA-binding EVs.26McKenzie A.J. Hoshino Hong N.H. Cha Franklin J.L. Coffey R.J. Patton J.G. Weaver A.M. KRAS-MEK signaling controls Ago2 exosomes.Cell 15: 978-987https://doi.org/10.1016/j.celrep.2016.03.085Abstract (251) profound regulatory natural occurrence AGO2-binding shRNAs great candidates class circRNAs.27Li Zheng Q. Bao Zhao He Circular enriched exosomes: biomarker diagnosis.Cell 25: 981-984https://doi.org/10.1038/cr.2015.82Crossref (1462) circRNAs single-stranded circular non-coding back splicing exons mRNAs.28Conn Pillman K.A. Toubia Conn V.M. Salmanidis C.A. Roslan Schreiber A.W. Gregory P.A. Goodall G.J. binding quaking formation circRNAs.Cell. 160: 1125-1134https://doi.org/10.1016/j.cell.2015.02.014Abstract (1298) Scholar,29Ragan Shirokikh N.E. Preiss Insights exonic RNA.Sci. 2048https://doi.org/10.1038/s41598-018-37037-0Crossref (74) Some express times amount circRNA compared protein-coding mRNA, functional role, includes regulation absorbing miRNAs, competition pre-mRNA splicing, and, rarely, templates translation.30Meng Feng Tang CircRNA: novel cancer.Mol. Cancer. 16: 94https://doi.org/10.1186/s12943-017-0663-2Crossref (978) lack 5′ ends protects degradation exonucleases, ultimately confers longer lifespan transcripts cytoplasm RNAs.31Liu Khanabdali Kalionis Tai Xia RNAs: isolation, characterization role diseases.RNA 14: 1715-1721https://doi.org/10.1080/15476286.2017.1367886Crossref (78) confirmed negative relation proliferation concentration, allegedly diluted daughter proliferation. Recently, ratio linear higher cells, indicating mechanism.32Lasda Parker Co-precipitate vesicles: possible mechanism clearance.PLoS One. e0148407https://doi.org/10.1371/journal.pone.0148407Crossref (260) highly EV-packed partially cancers; (exo-circRNAs) considered primarily biomarkers screening early onset.32Lasda Scholar,33Du W.W. Fang Dhaliwal Yang Yee B.B. Promotion tumor progression transmission circSKA3.Mol. Ther. Nucleic Acids. 27: 276-292https://doi.org/10.1016/j.omtn.2021.11.027Abstract (7) due increased stability, support translation typical mRNA.34Wesselhoeft R.A. Kowalski P.S. Anderson D.G. potent 2629https://doi.org/10.1038/s41467-018-05096-6Crossref (240) internal ribosome entry site (IRES) interest.34Wesselhoeft persist one approach generating enhanced long-term expression. Such application would especially useful treatments extend exposure antigens or, generally, out dose. occurring open reading frame (ORF)-possessing minority yet capable translation, coding capacity.35Miao Ni Coding circRNAs: discoveries challenges.PeerJ. e10718https://doi.org/10.7717/peerj.10718Crossref Wesselhoeft achieved robust luciferase, EGFP, erythropoietin, CRISPR-associated endonuclease 9 (Cas9) transfection self-splicing intron-induced HEK293 cells.34Wesselhoeft Qu created severe acute respiratory syndrome coronavirus (SARS-CoV-2) spike performed experiments mice test immunization capacity encapsulated LNPs.36Qu Yi Zhang Tian al.Circular against variants.Cell. 185: 1728-1744.e16https://doi.org/10.1016/j.cell.2022.03.044Abstract Mice treated antibodies T responses similar those counterparts mRNA.36Qu Overall, results suggest make mRNAs improve general efficacy therapies treating infectious Ideally, code long-lasting allows developed means unbound CRY2 plant changes conformation blue light, CIBN truncated version CIB1, affinity its excited form.37Kennedy Hughes Peteya L.A. Schwartz J.W. Ehlers Tucker C.L. Rapid blue-light-mediated induction living Methods. 2010; 7: 973-975https://doi.org/10.1038/nmeth.1524Crossref (749) CIB1 attached cytosolic tail marker CD9 reporter mCherry GFP.38Yim Ryu S.W. Choi Lee Kim Shaker M.R. Sun Park al.Exosome engineering intracellular soluble optically reversible protein-protein module.Nat. 12277https://doi.org/10.1038/ncomms12277Crossref (318) named EXPLOR, cargo-CRY2 when exposed light. absence complex freely available Using approach, successfully Cre recombinase nuclear κB (NF-κB) suppressor srIκB EVs.39Choi Mirzaaghasi Heo Y.N. Shin Cho E.S. Song Chung Yook Yoo T.H. Exosome-based super-repressor IkappaBalpha relieves sepsis-associated organ damage mortality.Sci. Adv. eaaz6980https://doi.org/10.1126/sciadv.aaz6980Crossref (72) Based model, Osteikoetxea tested whether Cas9 systems heterodimerization activating stimulus.40Osteikoetxea Silva Lázaro-Ibáñez Salmond Shatnyeva Stein Schick Wren Lindgren Firth al.Engineered editing tool.J. e12225https://doi.org/10.1002/jev2.12225Crossref (5) PHIB PIF6, 630 nm molecule phycocyanobilin, VVD nanomagnets finally FKBP FRB, rapamycin. group CRY2-CIB1 resulted highest fractions, 20 per EV.40Osteikoetxea noteworthy observation study data MysPalm advantageous tetraspanin markers CD9. Two possib

Language: Английский

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Methods of the Large-Scale Production of Extracellular Vesicles

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(18), P. 10522 - 10522

Published: Sept. 10, 2022

To date, extracellular vesicles (EVs) have been extensively investigated as potential substitutes for cell therapy. Research has suggested their ability to overcome serious risks associated with the application of these cells. Although, translation EVs into clinical practice is hampered by lack a cheap reasonable way obtain clinically relevant number EVs, an available method large-scale production ensures vesicles’ integrity, preserves biological activity, and they are well reproducible, providing homogeneity product from batch batch. In this review, advances in development methods increase discussed. The existing approaches can be divided following: (1) those based on increasing natural creating using high capacity “cell factories”, (2) induction secretion under various stressors, (3) fragmentation creation biomimetic vesicles. aim review stimulate introduction draw attention new large scale.

Language: Английский

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