Overcoming immunotherapy resistance in colorectal cancer through nano-selenium probiotic complexes and IL-32 modulation

IF 12.8 1区医学 Q1 ENGINEERING, BIOMEDICAL

Biomaterials Pub Date : 2025-03-01 DOI:10.1016/j.biomaterials.2025.123233

Shiquan Li, Tao Liu, Chenyao Li, Zhiyuan Zhang, Jiantao Zhang, Di Sun

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引用次数: 0

Abstract

Background and objective

Colorectal cancer (CRC) is a major global health burden, with immunotherapy often limited by immune tolerance and resistance. This study introduces an innovative approach using Selenium Nanoparticles-Loaded Extracellular Vesicles combined with Interleukin-32 and Engineered Probiotic Escherichia coli Nissle 1917 (SeNVs@NE-IL32-EcN) to enhance CD8⁺ T cell-mediated immune responses and overcome immunotherapy resistance.

Methods

Single-cell RNA sequencing (scRNA-seq) and transcriptomic analyses were performed to identify key immune cells and regulators involved in CRC immunotherapy resistance, focusing on CD8⁺ T cells and the regulatory factor IL32. A humanized xenograft mouse model was used to evaluate the impact of IL32 and SeNVs@NE-IL32-EcN on tumor growth and immune responses. The SeNVs@NE-IL32-EcN complex was synthesized through a reverse micelle method and functionalized using extracellular vesicles. Its morphology, size, antioxidant activity, and safety were characterized using electron microscopy, dynamic light scattering (DLS), and in vitro co-culture assays.

Results

Single-cell analyses revealed a significant reduction in CD8⁺ T cell infiltration in immunotherapy-resistant CRC patients. IL32 was identified as a key regulator enhancing CD8⁺ T cell cytotoxic activity through granzyme B and IFN-γ secretion. Treatment with SeNVs@NE-IL32-EcN significantly improved the proliferation and activity of CD8⁺ T cells and reduced tumor progression in humanized mouse models. In vitro and in vivo results demonstrated the complex's biocompatibility, antioxidant properties, and ability to enhance CRC immunotherapy while mitigating immune tolerance.

Conclusion

SeNVs@NE-IL32-EcN offers a novel nano-biomaterial strategy that integrates nanotechnology and probiotic therapy to enhance CD8⁺ T cell-mediated immunity and overcome CRC immunotherapy resistance. This study lays the foundation for future therapeutic applications in cancer treatment by advancing immune-modulating biomaterials.

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来源期刊

Biomaterials 工程技术-材料科学：生物材料

CiteScore

26.00

自引率

2.90%

发文量

565

审稿时长

46 days

期刊介绍： Biomaterials is an international journal covering the science and clinical application of biomaterials. A biomaterial is now defined as a substance that has been engineered to take a form which, alone or as part of a complex system, is used to direct, by control of interactions with components of living systems, the course of any therapeutic or diagnostic procedure. It is the aim of the journal to provide a peer-reviewed forum for the publication of original papers and authoritative review and opinion papers dealing with the most important issues facing the use of biomaterials in clinical practice. The scope of the journal covers the wide range of physical, biological and chemical sciences that underpin the design of biomaterials and the clinical disciplines in which they are used. These sciences include polymer synthesis and characterization, drug and gene vector design, the biology of the host response, immunology and toxicology and self assembly at the nanoscale. Clinical applications include the therapies of medical technology and regenerative medicine in all clinical disciplines, and diagnostic systems that reply on innovative contrast and sensing agents. The journal is relevant to areas such as cancer diagnosis and therapy, implantable devices, drug delivery systems, gene vectors, bionanotechnology and tissue engineering.