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Photo-Controlled MUC1 Ablation via Steric Locking of Turn-On Reactors Enhances Pyroptosis-Immunotherapy of Triple
Huocheng Yang1, Yingqi Liu1, Menghuan Li1
1School of Life Science, Chongqing University, Chongqing, 400044, P. R. China.
Abstract:
Mucin 1 (MUC1) is aberrantly upregulated in triple-negative breast cancer (TNBC) cells and presents major roles in orchestrating TNBC pathogenesis and therapeutic resistance. Herein, a bioorthogonal MUC1-binding strategy is reported to install MUC1-lockable aggregation-induced emission theranostic reactor (AIETR) onto MUC1 for pyroptosis-immunotherapy while enabling in situ MUC1 visualization. TNBC-bearing hosts are first treated with 1,3,4-O-acetyl-N-azidoacetylmannosamine-containing bioresponsive nanoassemblies to generate azido groups on MUC1 via sialic acid metabolism pathway. Dibenzocyclooctyne and MUC1-binding aptamer arms in AIETR can separately bind with azide moieties and aptamer binding domains in MUC1 of glycoengineered TNBC cells and restrict intramolecular rotation to activate their AIE-dependent reactive oxygen species (ROS) generation and fluorescence imaging capacity. The proximity-dependent ROS damage abolishes membrane MUC1 to activate pyroptosis cascades. Moreover, treatment-enabled MUC1 inactivation also ameliorates MUC1-dependent immunosuppression in TNBC microenvironment to boost anti-TNBC immunity. This study offers an effective approach for precision TNBC theranostics in the clinic.
Insights
This study introduces a novel theranostic reactor that targets Mucin 1 (MUC1) in triple-negative breast cancer (TNBC). This approach visualizes MUC1, triggers cell death via pyroptosis, and enhances anti-cancer immunity.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Immunotherapy
Background:
- Mucin 1 (MUC1) is overexpressed in triple-negative breast cancer (TNBC), contributing to disease progression and treatment resistance.
- Targeting MUC1 offers a potential strategy for TNBC theranostics.
Purpose of the Study:
- To develop a bioorthogonal MUC1-binding strategy for a theranostic reactor.
- To enable MUC1 visualization, pyroptosis induction, and immunotherapy in TNBC.
Main Methods:
- Engineered TNBC cells with azido groups on MUC1 using bioresponsive nanoassemblies.
- Utilized a MUC1-lockable aggregation-induced emission theranostic reactor (AIETR) with dibenzocyclooctyne and aptamer arms.
- Activated AIETR for reactive oxygen species (ROS) generation, fluorescence imaging, and MUC1 inactivation.
Main Results:
- Successful MUC1 visualization and in situ targeting.
- AIETR activation led to ROS-mediated MUC1 damage, initiating pyroptosis.
- MUC1 inactivation reduced immunosuppression, enhancing anti-tumor immunity.
Conclusions:
- The developed AIETR strategy effectively targets MUC1 in TNBC.
- This approach shows promise for pyroptosis-immunotherapy and precision theranostics in TNBC.
