In situ repurposing of dendritic cells with CRISPR/Cas9-based nanomedicine to induce transplant tolerance

Zhang, Yue; Shen, Song; Gui, Zhao; Xu, Cong; Zhang, Hou-Bing; Luo, Ying-Li; Cao, Zhi-Ting; Shi, Jia; Zhao, Zhibin; Lian, Zhe‐Xiong; Wang, Jun

doi:10.1016/j.biomaterials.2019.119302

Cited by 72 publications

(55 citation statements)

References 55 publications

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“…PLGA NPs have been used extensively to deliver immunomodulators and prevent allograft rejection 265 ; PLGA NPs anchored to a hydrogel allow for local and sustained (28-day) delivery of tacrolimus, a common immunosuppressant 266 . For more long-term effects, genetic engineering -reprogramming immune cells at the genomic level -could be effective 267 .…”

Section: Immune Suppressionmentioning

confidence: 99%

Engineering precision nanoparticles for drug delivery

Mitchell

Billingsley

Haley

et al. 2020

Nat Rev Drug Discov

4,092

2,814

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In recent years, the development of nanoparticles has expanded into a broad range of clinical applications. Nanoparticles have been developed to overcome the limitations of free therapeutics and navigate biological barriers — systemic, microenvironmental and cellular — that are heterogeneous across patient populations and diseases. Overcoming this patient heterogeneity has also been accomplished through precision therapeutics, in which personalized interventions have enhanced therapeutic efficacy. However, nanoparticle development continues to focus on optimizing delivery platforms with a one-size-fits-all solution. As lipid-based, polymeric and inorganic nanoparticles are engineered in increasingly specified ways, they can begin to be optimized for drug delivery in a more personalized manner, entering the era of precision medicine. In this Review, we discuss advanced nanoparticle designs utilized in both non-personalized and precision applications that could be applied to improve precision therapies. We focus on advances in nanoparticle design that overcome heterogeneous barriers to delivery, arguing that intelligent nanoparticle design can improve efficacy in general delivery applications while enabling tailored designs for precision applications, thereby ultimately improving patient outcome overall.

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Section: Immune Suppressionmentioning

confidence: 99%

Engineering precision nanoparticles for drug delivery

Mitchell

Billingsley

Haley

et al. 2020

Nat Rev Drug Discov

4,092

2,814

View full text Add to dashboard Cite

show abstract

“…This method is capable of delivering of delivering Cas9 mRNA (mCas9) and a guide RNA targeting the costimulatory molecule CD40 (gCD40) both in vivo and in vitro. CD40 knockdown significantly reduced T-cell activation, thus alleviating graft damage and prolonging graft survival (88).…”

Section: Dendritic Cellsmentioning

confidence: 99%

“…Dendritic cells (DCs) play a critical role in T-cell response instructions, with triple knockout established as proof of concept (118). A similar approach is used to target the costimulatory molecule CD40, whose disruption significantly inhibits T-cell activation, thus reducing graft damage and prolonging graft survival (88). Macrophages can also be edited using CRISPR-CAS9 by targeting USP7 and USP47, two genes that regulate inflammasome activation (119).…”

Section: Advances In Genetic Engineering Of Immune Cellsmentioning

confidence: 99%

Using Gene Editing Approaches to Fine-Tune the Immune System

et al. 2020

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Genome editing technologies not only provide unprecedented opportunities to study basic cellular system functionality but also improve the outcomes of several clinical applications. In this review, we analyze various gene editing techniques used to finetune immune systems from a basic research and clinical perspective. We discuss recent advances in the development of programmable nucleases, such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeat (CRISPR)-Cas-associated nucleases. We also discuss the use of programmable nucleases and their derivative reagents such as base editing tools to engineer immune cells via gene disruption, insertion, and rewriting of T cells and other immune components, such natural killers (NKs) and hematopoietic stem and progenitor cells (HSPCs). In addition, with regard to chimeric antigen receptors (CARs), we describe how different gene editing tools enable healthy donor cells to be used in CAR T therapy instead of autologous cells without risking graft-versus-host disease or rejection, leading to reduced adoptive cell therapy costs and instant treatment availability for patients. We pay particular attention to the delivery of therapeutic transgenes, such as CARs, to endogenous loci which prevents collateral damage and increases therapeutic effectiveness. Finally, we review creative innovations, including immune system repurposing, that facilitate safe and efficient genome surgery within the framework of clinical cancer immunotherapies.

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“…Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) is emerging as a powerful tool for engineering the genome in diverse organisms. Zhang et al encapsulated Cas9 mRNA (mCas9) and a guide RNA targeting CD40 (gCD40) with nanoparticles ( 139 ). mCas9/gCD40 was effectively delivered into DCs and disrupted CD40 signaling, significantly protecting grafts from acute rejection-mediated injury and prolonging graft survival.…”

Section: In Situ Targeting Of Dcregsmentioning

confidence: 99%

Manipulation of Regulatory Dendritic Cells for Induction Transplantation Tolerance

Que

Guo

2020

Front. Immunol.

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Current organ transplantation therapy is life-saving but accompanied by well-recognized side effects due to post-transplantation systematic immunosuppressive treatment. Dendritic cells (DCs) are central instigators and regulators of transplantation immunity and are responsible for balancing allograft rejection and tolerance. They are derived from monocyte-macrophage DC progenitors originating in the bone marrow and are classified into different subsets based on their developmental, phenotypical, and functional criteria. Functionally, DCs instigate allograft immunity by presenting donor antigens to alloreactive T cells via direct, indirect, and semidirect recognition pathways and provide essential signaling for alloreactive T cell activation via costimulatory molecules and pro-inflammatory cytokines. Regulatory DCs (DCregs) are characterized by a relatively low expression of major histocompatibility complex, costimulatory molecules, and altered cytokine production and exert their regulatory function through T cell anergy, T cell deletion, and regulatory T cell induction. In rodent transplantation studies, DCreg-based therapy, by in situ targeting or infusion of ex vivo generated DCregs, exhibits promising potential as a natural, well-tolerated, organ-specific therapeutic strategy for promoting lasting organ-specific transplantation tolerance. Recent early-phase studies of DCregs have begun to examine the safety and efficacy of DCreg-induced allograft tolerance in living-donor renal or liver transplantations. The present review summarizes the basic characteristics, function, and translation of DCregs in transplantation tolerance induction.

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In situ repurposing of dendritic cells with CRISPR/Cas9-based nanomedicine to induce transplant tolerance

Cited by 72 publications

References 55 publications

Engineering precision nanoparticles for drug delivery

Engineering precision nanoparticles for drug delivery

Using Gene Editing Approaches to Fine-Tune the Immune System

Manipulation of Regulatory Dendritic Cells for Induction Transplantation Tolerance

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