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Targeted gene delivery systems for T-cell engineering

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Abstract

T lymphocytes are indispensable for the host systems of defense against pathogens, tumors, and environmental threats. The therapeutic potential of harnessing the cytotoxic properties of T lymphocytes for antigen-specific cell elimination is both evident and efficacious. Genetically engineered T-cells, such as those employed in CAR-T and TCR-T cell therapies, have demonstrated significant clinical benefits in treating cancer and autoimmune disorders. However, the current landscape of T-cell genetic engineering is dominated by strategies that necessitate in vitro T-cell isolation and modification, which introduce complexity and prolong the development timeline of T-cell based immunotherapies. This review explores the complexities of gene delivery systems designed for T cells, covering both viral and nonviral vectors. Viral vectors are known for their high transduction efficiency, yet they face significant limitations, such as potential immunogenicity and the complexities involved in large-scale production. Nonviral vectors, conversely, offer a safer profile and the potential for scalable manufacturing, yet they often struggle with lower transduction efficiency. The pursuit of gene delivery systems that can achieve targeted gene transfer to T cell without the need for isolation represents a significant advancement in the field. This review assesses the design principles and current research progress of such systems, highlighting the potential for in vivo gene modification therapies that could revolutionize T-cell based treatments. By providing a comprehensive analysis of these systems, we aim to contribute valuable insights into the future development of T-cell immunotherapy.

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Abbreviations

aAPC:

Artificial antigen-presenting cell

AAV:

Adeno-associated virus

ABE:

Adenine base editor

BCMA:

B-cell maturation antigen

CAR-T therapy:

Chimeric antigen receptor T-cell therapy

CBE:

Cytosine base editor

CD19:

The cluster of differentiation 19

CPPs:

Cell-penetrating peptides

CRISPR:

Clustered regularly interspaced short palindromic repeats

CRS:

Cytokine release syndrome

CTL:

Cytotoxic T lymphocyte

DARPins:

Designed ankyrin repeat proteins

EBV:

Epstein-Barr virus

EGFR:

Epidermal growth factor receptor

FDA:

Food and drug administration

HDR:

Homology-directed repair

HIV:

Human immunodeficiency virus

ITR:

Inverted terminal repeat

LDLR:

Low-density lipoprotein receptor

LNP:

Lipid nanoparticle

LV:

Lentiviral vector

MHC:

Major histocompatibility complex

PB:

PiggyBac transposon system

RME:

Receptor-mediated endocytosis

SB system:

Sleeping Beauty transposon system

TAA:

Tumor-associated antigen

TCR-T therapy:

T-cell receptor engineered T-cell therapy

TIL therapy:

Tumor-infiltrating lymphocyte therapy

VSV-G:

Vesicular stomatitis virus G protein

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Images were created with BioRender.com.

Funding

This work was supported by the National Natural Science Foundation of China (81972878, 82172733), the Key Research and Development Program of Sichuan Province (2022ZDZX0024).

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W.W. conceived and presented the article idea and supervised the whole work. F.L.W. collected the data and wrote the first draft of the manuscript. Y.H. provided important suggestions for manuscript writing. J.Q.L. provided important suggestions for figure drawing. W.L.Z. provided important suggestions for figure drawing. All the authors participated in the work and approved the manuscript for publication.

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Correspondence to Wei Wang.

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Wang, F., Huang, Y., Li, J. et al. Targeted gene delivery systems for T-cell engineering. Cell Oncol. (2024). https://doi.org/10.1007/s13402-024-00954-6

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