Structure and Function of Cationic and Ionizable Lipids for Nucleic Acid Delivery

Pharmaceutical Research, Journal Year: 2023, Volume and Issue: 40(1), P. 27 - 46

Published: Jan. 1, 2023

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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Lipid nanoparticles (LNPs) for in vivo RNA delivery and their breakthrough technology for future applications

Advanced Drug Delivery Reviews, Journal Year: 2023, Volume and Issue: 200, P. 114990 - 114990

Published: July 7, 2023

Language: Английский

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mRNA-based vaccines and therapeutics: an in-depth survey of current and upcoming clinical applications

Journal of Biomedical Science, Journal Year: 2023, Volume and Issue: 30(1)

Published: Oct. 7, 2023

mRNA-based drugs have tremendous potential as clinical treatments, however, a major challenge in realizing this drug class will promise to develop methods for safely delivering the bioactive agents with high efficiency and without activating immune system. With regard mRNA vaccines, researchers modified structure enhance its stability promote systemic tolerance of antigenic presentation non-inflammatory contexts. Still, delivery naked mRNAs is inefficient results low levels antigen protein production. As such, lipid nanoparticles been utilized improve protect cargo from extracellular degradation. This advance was milestone development vaccines dispelled skepticism about technology yield clinically approved medicines. Following resounding success COVID-19, many other proposed treatment variety diseases. review begins discussion modifications vehicles, well factors that influence administration routes. Then, we summarize applications discuss further key points pertaining preclinical targeting wide range Finally, latest market trends future drugs.

Language: Английский

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Outlook of pandemic preparedness in a post-COVID-19 world

npj Vaccines, Journal Year: 2023, Volume and Issue: 8(1)

Published: Nov. 20, 2023

Abstract The COVID-19 pandemic was met with rapid, unprecedented global collaboration and action. Even still, the public health, societal, economic impact may be felt for years to come. risk of another occurring in next few decades is ever-present potentially increasing due trends such as urbanization climate change. While it difficult predict pathogen threat, making reasonable assumptions today evaluating prior efforts plan respond disease outbreaks pandemics enable a more proactive, effective response future. Lessons from influenza preparedness underscore importance strengthening surveillance systems, investing early-stage research on pathogens development platform technologies, diversifying plans across range tactics earlier access safe interventions pandemic. Further, sustaining robust vaccine manufacturing capacity built because will keep ready rapid These actions not successful without improved coordination collaboration. Everyone, including biopharmaceutical industry, has role play preparedness, working together ensure that most lives are saved

Language: Английский

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Strategies to reduce the risks of mRNA drug and vaccine toxicity

Nature Reviews Drug Discovery, Journal Year: 2024, Volume and Issue: 23(4), P. 281 - 300

Published: Jan. 23, 2024

Language: Английский

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Approved Nanomedicine against Diseases

Pharmaceutics, Journal Year: 2023, Volume and Issue: 15(3), P. 774 - 774

Published: Feb. 26, 2023

Nanomedicine is a branch of medicine using nanotechnology to prevent and treat diseases. Nanotechnology represents one the most effective approaches in elevating drug‘s treatment efficacy reducing toxicity by improving drug solubility, altering biodistribution, controlling release. The development materials has brought profound revolution medicine, significantly affecting various major diseases such as cancer, injection, cardiovascular experienced explosive growth past few years. Although clinical transition nanomedicine not very satisfactory, traditional drugs still occupy dominant position formulation development, but increasingly active have adopted nanoscale forms limit side effects improve efficacy. review summarized approved nanomedicine, its indications, properties commonly used nanocarriers nanotechnology.

Language: Английский

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Knife’s edge: Balancing immunogenicity and reactogenicity in mRNA vaccines

Experimental & Molecular Medicine, Journal Year: 2023, Volume and Issue: 55(7), P. 1305 - 1313

Published: July 10, 2023

Since the discovery of messenger RNA (mRNA), there have been tremendous efforts to wield them in development therapeutics and vaccines. During COVID-19 pandemic, two mRNA vaccines were developed approved record-breaking time, revolutionizing vaccine landscape. Although first-generation demonstrated over 90% efficacy, alongside strong immunogenicity humoral cell-mediated immune responses, their durability has lagged compared long-lived vaccines, such as yellow fever vaccine. worldwide vaccination campaigns saved lives estimated tens millions, side effects, ranging from mild reactogenicity rare severe diseases, reported. This review provides an overview mechanistic insights into responses adverse effects documented primarily for Furthermore, we discuss perspectives this promising platform challenges balancing effects.

Language: Английский

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Lipid Nanoparticles Optimized for Targeting and Release of Nucleic Acid

Advanced Materials, Journal Year: 2023, Volume and Issue: 36(4)

Published: Aug. 7, 2023

Abstract Lipid nanoparticles (LNPs) are currently the most promising clinical nucleic acids drug delivery vehicles. LNPs prevent degradation of cargo during blood circulation. Upon entry into cell, specific components lipid can promote endosomal escape acids. These basic properties as acid carriers. As exhibit hepatic aggregation characteristics, enhancing targeting out liver is a crucial way to improve administrated in vivo. Meanwhile, loaded often considered inadequate, and therefore, much effort devoted intracellular release efficiency Here, different strategies efficiently deliver from concluded their mechanisms investigated. In addition, based on information that trials or have completed trials, issues necessary be approached translation discussed, which it hoped will shed light development LNP drugs.

Language: Английский

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‘Spikeopathy’: COVID-19 Spike Protein Is Pathogenic, from Both Virus and Vaccine mRNA

Biomedicines, Journal Year: 2023, Volume and Issue: 11(8), P. 2287 - 2287

Published: Aug. 17, 2023

The COVID-19 pandemic caused much illness, many deaths, and profound disruption to society. production of ‘safe effective’ vaccines was a key public health target. Sadly, unprecedented high rates adverse events have overshadowed the benefits. This two-part narrative review presents evidence for widespread harms novel product mRNA adenovectorDNA is in attempting provide thorough overview arising from new technology that relied on human cells producing foreign antigen has pathogenicity. first paper explores peer-reviewed data counter attached these technologies. Spike protein pathogenicity, termed ‘spikeopathy’, whether SARS-CoV-2 virus or produced by vaccine gene codes, akin ‘synthetic virus’, increasingly understood terms molecular biology pathophysiology. Pharmacokinetic transfection through body tissues distant injection site lipid-nanoparticles viral-vector carriers means ‘spikeopathy’ can affect organs. inflammatory properties nanoparticles used ferry mRNA; N1-methylpseudouridine employed prolong synthetic function; biodistribution DNA codes translated spike proteins, autoimmunity via contribute harmful effects. reviews autoimmune, cardiovascular, neurological, potential oncological effects, autopsy spikeopathy. With gene-based therapeutic technologies planned, re-evaluation necessary timely.

Language: Английский

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