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Engineered Dendritic Cell-Derived Vesicles for T-Cell-Targeted Magnesium Delivery and Metabolic Reprogramming
Xiaoyu Yu1, Shuqi Chen1, Rong Sun1
1Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu 215123, China.
ACS Nano
|November 25, 2025
Summary
Engineered extracellular vesicles deliver magnesium ions (Mg2+) to restore exhausted T cells and enhance cancer immunotherapy when combined with immune checkpoint blockade.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- The tumor microenvironment (TME) suppresses anti-tumor immunity, limiting immunotherapy effectiveness.
- Magnesium ions (Mg2+) can enhance cytotoxic T lymphocyte (CD8+ T) activity but face delivery challenges.
- Existing Mg2+ carriers have poor biocompatibility and targeting, hindering therapeutic potential.
Purpose of the Study:
- To develop an engineered extracellular vesicle (EV)-based system for targeted Mg2+ delivery to enhance cancer immunotherapy.
- To investigate the immunomodulatory effects of Mg2+ delivered via engineered EVs on T-cell metabolism and function within the TME.
Main Methods:
- Genetically modified dendritic cells to overexpress MgtE (SLC41A1) for Mg2+ encapsulation into EVs (E-DEVs).
- Developed Mg2+-loaded E-DEVs (E-DEVs@Mg2+) for targeted delivery to tumor-draining lymph nodes (TDLNs).
- Assessed the impact of E-DEVs@Mg2+ on CD8+ T-cell metabolism (glycolysis, oxidative phosphorylation) and combined efficacy with immune checkpoint blockade.
Main Results:
- E-DEVs@Mg2+ demonstrated tropism for TDLNs and effectively modulated T-cell metabolism.
- Mg2+ delivery via E-DEVs restored metabolic fitness in exhausted CD8+ T cells by enhancing glycolysis and oxidative phosphorylation.
- Combination therapy of E-DEVs@Mg2+ with immune checkpoint blockade achieved synergistic tumor suppression.
Conclusions:
- Engineered dendritic cell-derived EVs (E-DEVs) serve as a biocompatible platform for targeted Mg2+ delivery.
- This strategy shows promise for metabolic reprogramming of exhausted T cells, overcoming TME-mediated immunosuppression.
- The developed approach offers a novel therapeutic avenue for enhancing cancer immunotherapy efficacy.
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