Engineering strategies to overcome the current roadblocks in CAR T cell therapy

Nature Reviews Clinical Oncology, Journal Year: 2019, Volume and Issue: 17(3), P. 147 - 167

Published: Dec. 17, 2019

Language: Английский

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CAR-NK cells: A promising cellular immunotherapy for cancer

EBioMedicine, Journal Year: 2020, Volume and Issue: 59, P. 102975 - 102975

Published: Aug. 24, 2020

Natural Killer (NK) cells and CD8+ cytotoxic T are two types of immune that can kill target through similar mechanisms. With the remarkable success chimeric antigen receptor (CAR)-engineered (CAR-T) for treating haematological malignancies, there is a rapid growing interest in developing CAR-engineered NK (CAR-NK) cancer therapy. Compared to CAR-T cells, CAR-NK could offer some significant advantages, including: (1) better safety, such as lack or minimal cytokine release syndrome neurotoxicity autologous setting graft-versus-host disease allogenic setting, (2) multiple mechanisms activating activity, (3) high feasibility 'off-the-shelf' manufacturing. be engineered diverse antigens, enhance proliferation persistence vivo, increase infiltration into solid tumours, overcome resistant tumour microenvironment, ultimately achieve an effective anti-tumour response. In this review, we focus on recent progress genetic engineering clinical application discuss current challenges future promise novel cellular immunotherapy cancer.

Language: Английский

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CRISPR-Based Therapeutic Genome Editing: Strategies and In Vivo Delivery by AAV Vectors

Cell, Journal Year: 2020, Volume and Issue: 181(1), P. 136 - 150

Published: April 1, 2020

Language: Английский

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CAR T Cell Therapy for Solid Tumors: Bright Future or Dark Reality?

Molecular Therapy, Journal Year: 2020, Volume and Issue: 28(11), P. 2320 - 2339

Published: Sept. 16, 2020

Chimeric antigen receptor (CAR) T cell therapy has garnered significant excitement due to its success for hematological malignancies in clinical studies leading the US Food and Drug Administration (FDA) approval of three CD19-targeted CAR products. In contrast, experience with solid tumors brain been less encouraging, only a few patients achieving complete responses. Clinical preclinical have identified multiple "roadblocks," including (1) limited array targetable antigens heterogeneous expression, (2) fitness survival before reaching tumor sites, (3) an inability cells efficiently traffic sites penetrate physical barriers, (4) immunosuppressive microenvironment. Herein, we review these challenges discuss strategies that investigators taken improve effector function adoptive immunotherapy tumors. Adoptive therapies utilizing expressing chimeric receptors (CARs) propelled forefront experimental their targeting range antigens, CD19, CD22, CD30, kappa, B maturation (BCMA).1Porter D.L. Levine B.L. Kalos M. Bagg A. June C.H. receptor-modified chronic lymphoid leukemia.N. Engl. J. Med. 2011; 365: 725-733Crossref PubMed Scopus (2158) Google Scholar, 2Grupp S.A. Barrett D. Aplenc R. Porter Rheingold S.R. Teachey D.T. Chew Hauck B. Wright J.F. et al.Chimeric acute 2013; 368: 1509-1518Crossref (1949) 3Maude S.L. Frey N. Shaw P.A. D.M. Bunin N.J. Gonzalez V.E. Zheng Z. Lacey S.F. sustained remissions 2014; 371: 1507-1517Crossref (2496) 4Fry T.J. Shah N.N. Orentas R.J. Stetler-Stevenson Yuan C.M. Ramakrishna S. Wolters P. Martin Delbrook C. Yates al.CD22-targeted induce remission B-ALL is naive or resistant immunotherapy.Nat. 2018; 24: 20-28Crossref (399) 5Gardner R.A. Finney O. Annesley Brakke H. Summers Leger K. Bleakley Brown Mgebroff Kelly-Spratt K.S. al.Intent-to-treat leukemia by CD19 defined formulation dose children young adults.Blood. 2017; 129: 3322-3331Crossref (11) 6Ramos C.A. Grover N.S. Beaven A.W. Lulla P.D. Wu M.F. Ivanova Wang T. Shea T.C. Rooney Dittus al.Anti-CD30 CAR-T relapsed refractory Hodgkin lymphoma.J. Clin. Oncol. 2020; (Published online July 23, 2020. 10.1200/JCO.20.01342)Crossref 7Ramos Savoldo Torrano V. Ballard Zhang Dakhova Liu E. Carrum G. Kamble R.T. Gee A.P. al.Clinical responses lymphocytes malignancy-associated κ light chains.J. Invest. 2016; 126: 2588-2596Crossref (134) 8Raje Berdeja Lin Y. Siegel Jagannath Madduri Liedtke Rosenblatt Maus M.V. Turka al.Anti-BCMA T-cell bb2121 myeloma.N. 2019; 380: 1726-1737Crossref (249) 9Turtle C.J. Hanafi L.A. Berger Hudecek Pender Robinson Hawkins Chaney Cherian Chen X. al.Immunotherapy non-Hodgkin's lymphoma ratio CD8+ CD4+ CD19-specific cells.Sci. Transl. 8: 355ra116Crossref (421) 10Kochenderfer J.N. Somerville R.P.T. Lu Yang J.C. Sherry R.M. Feldman McIntyre L. Bot Rossi Lam Rosenberg Long-duration diffuse large after anti-CD19 therapy.Mol. Ther. 25: 2245-2253Abstract Full Text PDF (114) Scholar The landscape malignancies, successes challenges, subject recent reviews.11Holstein Lunning M.A. hematologic malignancies: voyage progress.Clin. Pharmacol. 107: 112-122Crossref (0) 12Boyiadzis M.M. Dhodapkar Brentjens Kochenderfer Neelapu S.S. Maloney D.G. Grupp Mackall C.L. treatment perspective significance.J. Immunother. Cancer. 6: 137Crossref (48) 13Majzner R.G. lessons learned from first leg journey.Nat. 1341-1355Crossref (58) We therefore do not detail, except highlighting "lessons learned" as they relate tumors, First, can eradicate chemorefractory cancer regardless underlying oncogenic driver mutations; second, lymphodepleting chemotherapy at present sine qua non enable expansion persistence infused cells; third, inclusion least one co-stimulatory signaling domain critical success; fourth: loss variants emerged mechanism therapeutic failure, even are highly homogeneously expressed such CD19; fifth, side effects, cytokine release syndrome (CRS) neurotoxicity.11Holstein 14Neelapu Tummala Kebriaei Wierda W. Locke F.L. Jain Daver Gulbis A.M. Adkins al.Toxicity management therapy: size does fit "ALL".Nat. Rev. 15: 218Crossref 15Lee D.W. Santomasso B.D. Ghobadi Turtle Brudno Park J.H. Mead Pavletic al.ASTCT consensus grading neurologic toxicity associated immune cells.Biol. Blood Marrow Transplant. 625-638Abstract (307) contrast shown antitumor activity early phase testing despite variety target types.16Goff Morgan Robbins P.F. Restifo N.P. Y.C. al.Pilot trial transfer receptor-transduced EGFRvIII glioblastoma.J. 42: 126-135Crossref 17O'Rourke Nasrallah M.P. Desai Melenhorst J.J. Mansfield Morrissette J.J.D. Martinez-Lage Brem Shen al.A single peripherally EGFRvIII-directed mediates induces adaptive resistance recurrent glioblastoma.Sci. 9 (eaaa0984)PubMed 18Morgan Kitano Dudley M.E. Laurencot Case report serious adverse event following administration transduced recognizing ERBB2.Mol. 2010; 18: 843-851Abstract (1312) 19Lamers Sleijfer Vulto A.G. Kruit W.H. Kliffen Debets Gratama J.W. Stoter Oosterwijk Treatment metastatic renal carcinoma autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: experience.J. 2006; e20-e22Crossref (597) 20Lamers van Steenbergen Elzakker Krimpen Groot den Bakker CAIX CAR-engineered cells: evaluation on-target toxicity.Mol. 21: 904-912Abstract (359) 21Kershaw M.H. Westwood J.A. Parker L.L. Eshhar Mavroukakis White D.E. Wunderlich J.R. Canevari Rogers-Freezer I study on using gene-modified ovarian cancer.Clin. Cancer Res. 12: 6106-6115Crossref (733) 22Brown C.E. Alizadeh Starr Weng Wagner Naranjo Ostberg Blanchard M.S. Kilpatrick Simpson al.Regression glioblastoma therapy.N. 375: 2561-2569Crossref 23Ahmed Brawley V.S. Hegde Robertson Ghazi Gerken Ashoori Corder al.Human epidermal growth factor 2 (HER2)-specific HER2-positive sarcoma.J. 2015; 33: 1688-1696Crossref (444) 24Wang Tong Dai Guo Huang Lv Luo al.CD133-directed advanced metastasis trial.OncoImmunology. 7: e1440169Crossref (60) 25Thistlethwaite F.C. Gilham Guest R.D. Rothwell Pillai Burt D.J. Byatte A.J. Kirillova Valle Sharma S.K. al.The efficacy first-generation carcinoembryonic (CEACAM5)-specific poor transient pre-conditioning-dependent respiratory toxicity.Cancer Immunol. 66: 1425-1436Crossref (94) 26Ahmed Bielamowicz Kalra Landi Gray T.L. Diouf Wakefield al.HER2-specific virus-specific progressive glioblastoma: 1 dose-escalation trial.JAMA 3: 1094-1101Crossref (187) This failure most likely multifactorial includes design generation, expression (aka "antigen dilemma"), fitness, inefficient homing penetration (5) hostile microenvironment (TME) (Figure 1).27Rafiq Hackett C.S. Engineering overcome current roadblocks therapy.Nat. 17: 147-167Crossref (46) 28Rodriguez-Garcia Palazon Noguera-Ortega Powell Jr., Guedan hit microenvironment: escape.Front. 11: 1109Crossref 29Schmidts Making option tumors.Front. 9: 2593Crossref 30Knochelmann H.M. Smith A.S. Dwyer Wyatt Mehrotra Paulos tumors: blueprints building effective therapies.Front. 1740Crossref design, genetic approaches aforementioned roadblocks. Since allogeneic mainly explored studies, refer interested reader recently published reviews.31Depil Duchateau Mufti Poirot "Off-the-shelf" development challenges.Nat. Discov. 19: 185-199Crossref (47) Scholar,32Qasim Allogeneic leukemia.Am. Hematol. 94: S50-S54Crossref (10) also CRS neurotoxicity since several reviews covered this topic.14Neelapu Scholar,33Frey Cytokine therapy.Biol. e123-e127Abstract CARs modular consists antigen-binding domain, commonly single-chain variable fragment (scFv) derived monoclonal antibody (mAb), hinge transmembrane intracellular domain.27Rafiq Scholar,34Kuwana Asakura Utsunomiya Nakanishi Arata Itoh Nagase F. Kurosawa Expression composed immunoglobulin-derived V regions receptor-derived C regions.Biochem. Biophys. Commun. 1987; 149: 960-968Crossref (148) 35Gross Waks immunoglobulin-T-cell molecules functional antibody-type specificity.Proc. Natl. Acad. Sci. USA. 1989; 86: 10024-10028Crossref (724) 36Eshhar Gross Schindler Specific activation cytotoxic through chains consisting antibody-binding domains gamma zeta subunits immunoglobulin receptors.Proc. 1993; 90: 720-724Crossref (816) 37June Sadelain 379: 64-73Crossref (436) 38Dotti Gottschalk Brenner M.K. Design receptor-expressing cells.Immunol. 257: 107-126Crossref (256) addition scFvs, natural ligands cytokines peptides bind surface being domains.22Brown Scholar,39Shaffer D.R. Yi Chow K.K. Kakarla Spencer Dotti Kenney redirected CD70 CD70-positive malignancies.Blood. 117: 4304-4314Crossref Scholar,40Davies Foster Van Der Stegen S.J. Parente-Pereira A.C. Chiapero-Stanke Delinassios G.J. Burbridge S.E. Kao Bosshard-Carter al.Flexible ErbB dimers drive tumorigenesis engineered cells.Mol. 2012; 565-576Crossref (54) While recognize epitopes proteins major histocompatibility complex (MHC)-independent manner, scFvs incorporated into peptide context human leukocyte (HLA) molecule.41Ma Q. Garber H.R. He Tallis Ding Sergeeva Wood Salvado novel TCR-like specificity PR1/HLA-A2 effectively targets myeloid vitro when adult peripheral blood cord cells.Cytotherapy. 985-994Abstract 42Rafiq Purdon Daniyan A.F. Koneru Dao Scheinberg D.A. Optimized receptor-mimic directed toward Wilms antigen.Leukemia. 31: 1788-1797Crossref 43Maus Plotkin Jakka Stewart-Jones Rivière I. Merghoub Wolchok Renner An MHC-restricted antibody-based requires affinity maintain specificity.Mol. Oncolytics. 1-9PubMed approach allows molecules, it renders recognition dependent particular HLA type, restricting application subset patients. addition, become sensitive decreased defects processing pathway, both pathways used actively evade responses.44Töpfer Kempe Müller Schmitz Bachmann Cartellieri Schackert Temme Tumor evasion surveillance.J. Biomed. Biotechnol. 2011: 918471Crossref First-generation contained utilized CD3ζ.37June Scholar,38Dotti optimal relies co-stimulation, were included CARs. Initial focused canonical CD28 41BB.37June then, broad explored, OX40, CD27, ICOS.37June Scholar,45Rafiq Yeku O.O. Jackson H.J. Leeuwen Drakes Song Miele Li al.Targeted delivery PD-1-blocking scFv enhances anti-tumor vivo.Nat. 36: 847-856Crossref (161) 46Hombach A.A. Abken Costimulation revisited response benefits combined CD28-OX40 signalling.Int. 2935-2944Crossref (93) 47Collinson-Pautz M.R. Chang W.C. Khalil Crisostomo P.Y. Mahendravada Shinners Brandt al.Constitutively active MyD88/CD40 costimulation malignancies.Leukemia. 2195-2207Crossref (14) 48Guedan Madar Carpenito McGettigan Frigault M.J. Lee Posey A.D. Scholler al.ICOS-based program bipolar TH17/TH1 cells.Blood. 124: 1070-1080Crossref (162) 49Nair J.B. Tsao S.T. Zhu Slayton W.B. Moreb J.S. Dong L.J. Functional improvement intrinsic interleukin-15Rα signaling.Curr. Gene 40-53Crossref (7) 41BB co-stimulation extensively studied, detailed phosphoproteomic single-cell RNA sequencing (RNA-seq) analyses.50Salter A.I. Ivey Kennedy Voillet Rajan Alderman E.J. Voytovich U.J. Sommermeyer al.Phosphoproteomic analysis reveals kinetic quantitative differences affect function.Sci. Signal. eaat6753Crossref 51Boroughs Larson R.C. Marjanovic N.D. Gosik Castano C.B.M. Lorrey Ashenberg Jerby Hofree distinct transcriptional bearing 4-1BB revealed scRNA-seq.Mol. 25, 2020)https://doi.org/10.1016/j.ymthe.2020.07.023Abstract 52Xhangolli Dura Kim Xiao Fan Single-cell mixed TH1/TH2 independent differentiation.Genomics Proteomics Bioinformatics. 129-139Crossref (13) They activate different within cells, promoting glycolytic metabolism memory phenotype, signaling, which oxidative central phenotype.53Kawalekar O.U. O' Connor R.S. Fraietta Patel P.R. Keith al.Distinct coreceptors regulates specific impacts cells.Immunity. 44: 712Abstract (36) Depending number either designated second (one domain) third (two domains) generation. benefit two model-dependent.54Quintarelli Orlando Boffa Guercio Polito V.A. Petretto Lavarello Sinibaldi Weber Del Bufalo al.Choice costimulatory determines neuroblastoma.OncoImmunology. e1433518Crossref (37) Scholar,55Zhao Condomines der S.J.C. Perna Kloss C.C. Gunset Structural rejection kinetics cells.Cancer Cell. 28: 415-428Abstract (288) Results study, comparing CD28-CAR versus CD28.41BB-CAR suggest third-generation endow greater ability expand infusion humans.56Ramos Rouce Reyna Narala Vyas Mehta al.In vivo fate second- lymphomas.Mol. 26: 2727-2737Abstract (52) Optimizing remains challenge there intricate interplay between (antigen nonfunctional components (hinge CARs.57Guest R.E. Cheadle Arnold O'Neill Irlam Chester K.A. Kemshead J.T. role extracellular spacer receptors: four antigens.J. 2005; 203-211Crossref Scholar,58Majzner Rietberg S.P. Sotillo Vachharajani V.T. Labanieh Myklebust Kadapakkam E.W. Tousley al.Tuning density requirement activity.Cancer 10: 702-723Crossref (17) location epitope targeted molecule activity.59Hudecek Lupo-Stanghellini M.T. Kosasih P.L. Jensen M.C. Rader Riddell Receptor modifications ROR1-specific cells.Clin. 3153-3164Crossref (246) For example, proximal plasma membrane than distal epitopes.57Guest Scholar,59Hudecek Scholar,60James Greenberg Till B.G. Raubitschek Forman Press O.W. Antigen sensitivity CD22-specific TCR modulated distance membrane.J. 2008; 180: 7028-7038Crossref (126) Studies highlighted too much detrimental function. mutated immunoreceptor tyrosine-based motifs (ITAMs) CD3ζ chain improved function.61Feucht Sun Eyquem Ho Y.J. Zhao Leibold Dobrin Cabriolu Hamieh Calibration potential directs alternative fates potency.Nat. 82-88Crossref (81) excessive effects,62Wijewarnasuriya Bebernitz Lopez A.V. Rafiq Excessive leads dysfunction adoptively transferred 732-742Crossref mutations YMXM motif reduce function.63Guedan Casado-Medrano Wing Young Single residue CD28-costimulated limits long-term durability.J. 130: 3087-3097Crossref (12) activation, baseline tonic) activity.64Long A.H. Haso W.M. Shern Wanhainen K.M. Murgai Ingaramo J.P. Walker Kohler Venkateshwara V.R. al.4-1BB ameliorates exhaustion induced tonic receptors.Nat. 581-590Crossref (528) Scholar,65Gomes-Silva Mukherjee Srinivasan Krenciute Cabral J.M.S. Orange Mamonkin Tonic impedes vector-dependent.Cell Rep. 17-26Abstract (80) Recently, studying immunological synapse formed correlated formation effectiveness.66Xiong Kang Hsu Y.H. Jang Qin Immunological predicts effectiveness 963-975Abstract (35) Scholar,67Davenport Cross Watson Liao Shi Prince Beavis Trapani Kershaw Ritchie D.S. form nonclassical potent synapses driving rapid cytotoxicity.Proc. 115: E2068-E2076Crossref (69) Lastly, limit

Language: Английский

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Tailoring Materials for Modulation of Macrophage Fate

Advanced Materials, Journal Year: 2021, Volume and Issue: 33(12)

Published: Feb. 9, 2021

Human immune system acts as a pivotal role in the tissue homeostasis and disease progression. Immunomodulatory biomaterials that can manipulate innate immunity adaptive hold great promise for broad range of prophylactic therapeutic purposes. This review is focused on design strategies principles immunomodulatory from standpoint materials science to regulate macrophage fate, such activation, polarization, adhesion, migration, proliferation, secretion. It offers comprehensive survey discussion tunability material designs regarding physical, chemical, biological, dynamic cues modulating response. The tailorable encompasses surface properties, topography, mechanics, composition, dynamics. representative immunoengineering applications selected herein demonstrate how macrophage-immunomodulating are being exploited cancer immunotherapy, infection regeneration, inflammation resolution, vaccination. A perspective future research directions immunoregulatory also provided.

Language: Английский

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Chimeric antigen receptor natural killer (CAR-NK) cell design and engineering for cancer therapy

Journal of Hematology & Oncology, Journal Year: 2021, Volume and Issue: 14(1)

Published: May 1, 2021

Abstract Due to their efficient recognition and lysis of malignant cells, natural killer (NK) cells are considered as specialized immune that can be genetically modified obtain capable effector for adoptive cellular treatment cancer patients. However, biological technical hurdles related gene delivery into NK have dramatically restrained progress. Recent technological advancements, including improved cell expansion techniques, chimeric antigen receptors (CAR), CRISPR/Cas9 editing enhanced viral transduction electroporation, endowed comprehensive generation characterization cells. These promising developments assist scientists physicians design better applications in clinical therapy. Notably, redirecting using CARs holds important promise immunotherapy. Various preclinical a limited number studies CAR-NK show results: elimination target without side effects, such cytokine release syndrome neurotoxicity which seen CAR-T therapies. In this review, we focus on the details technology, safe CAR constructs associated engineering techniques: vehicles deliver CAR-containing transgene, detection methods CARs, well sources expansion. We summarize current literature include valuable lessons learned from field. This review also provides an outlook how these approaches may transform products protocols treatment.

Language: Английский

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Lipid Nanoparticle (LNP) Enables mRNA Delivery for Cancer Therapy

Advanced Materials, Journal Year: 2023, Volume and Issue: 35(51)

Published: May 17, 2023

Abstract Messenger RNA (mRNA) has received great attention in the prevention and treatment of various diseases due to success coronavirus disease 2019 (COVID‐19) mRNA vaccines (Comirnaty Spikevax). To meet therapeutic purpose, it is required that must enter target cells express sufficient proteins. Therefore, development effective delivery systems necessary crucial. Lipid nanoparticle (LNP) represents a remarkable vehicle indeed accelerated applications humans, as several mRNA‐based therapies have already been approved or are clinical trials. In this review, focus on mRNA‐LNP‐mediated anticancer therapy. It summarizes main strategies mRNA‐LNP formulations, discusses representative approaches cancer, points out current challenges possible future directions research field. hoped these delivered messages can help further improve application technology cancer

Language: Английский

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Sleeping Beauty–engineered CAR T cells achieve antileukemic activity without severe toxicities

Journal of Clinical Investigation, Journal Year: 2020, Volume and Issue: 130(11), P. 6021 - 6033

Published: Aug. 11, 2020

BACKGROUND. Chimeric antigen receptor (CAR) T cell immunotherapy has resulted in complete remission (CR) and durable response highly refractory patients. However, logistical complexity high costs of manufacturing autologous viral products limit CAR availability.

Language: Английский

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Highly efficient CD4+ T cell targeting and genetic recombination using engineered CD4+ cell-homing mRNA-LNPs

Molecular Therapy, Journal Year: 2021, Volume and Issue: 29(11), P. 3293 - 3304

Published: June 4, 2021

Nucleoside-modified messenger RNA (mRNA)-lipid nanoparticles (LNPs) are the basis for first two EUA (Emergency Use Authorization) COVID-19 vaccines. The use of nucleoside-modified mRNA as a pharmacological agent opens immense opportunities therapeutic, prophylactic and diagnostic molecular interventions. In particular, mRNA-based drugs may specifically modulate immune cells, such T lymphocytes, immunotherapy oncologic, infectious other conditions. key challenge, however, is that cells notoriously resistant to transfection by exogenous mRNA. Here, we report conjugating CD4 antibody LNPs enables specific targeting interventions CD4+ including cells. After systemic injection in mice, CD4-targeted radiolabeled mRNA-LNPs accumulated spleen, providing ∼30-fold higher signal reporter isolated from spleen compared with non-targeted mRNA-LNPs. Intravenous loaded Cre recombinase-encoding provided dose-dependent loxP-mediated genetic recombination, resulting gene expression about 60% 40% lymph nodes, respectively. cell phenotyping showed uniform subpopulations, no variability uptake naive, central memory, effector efficient established this study provides platform technology devastating conditions HIV cure.

Language: Английский

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Rethinking CRITID Procedure of Brain Targeting Drug Delivery: Circulation, Blood Brain Barrier Recognition, Intracellular Transport, Diseased Cell Targeting, Internalization, and Drug Release

Advanced Science, Journal Year: 2021, Volume and Issue: 8(9)

Published: Feb. 24, 2021

Abstract The past decades have witnessed great progress in nanoparticle (NP)‐based brain‐targeting drug delivery systems, while their therapeutic potentials are yet to be fully exploited given that the majority of them lost during process. Rational design systems requires a deep understanding entire process along with issues they may encounter. Herein, this review first analyzes typical systemically administrated NPs‐based system and proposes six‐step CRITID cascade: circulation systemic blood, recognizing receptor on blood‐brain barrier (BBB), intracellular transport, diseased cell targeting after entering into parenchyma, internalization by cells, finally release. By dissecting six steps, seeks provide restrict efficiency as well specific requirements guarantee minimal loss at each step. Currently developed strategies used for troubleshooting these reviewed some state‐of‐the‐art features meeting highlighted. cascade can serve guideline designing more efficient systems.

Language: Английский

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