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In Situ Activating a Protein-Complexed Quenched Probe via Alkaline Phosphatase Response for Pyroptosis-Mediated
Jiangtao Geng1, Jie Sun1, Ling-Hong Xiong2
1State Key Laboratory of Bioinspired Interfacial Materials Science, The Key Lab of Health Chemistry and Molecular Diagnosis of Suzhou, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, China.
Abstract:
In situ synthesis of therapeutic agents and activation of immune effect within tumor cells are highly desired for precision cancer theranostics. Intracellular reaction and aggregation triggered by tumor-specific biomarkers represent a potent strategy to activate therapeutics and modulate immune responses. Here, we designed a protein-complexed quenched probe that specifically and sensitively responded to the abnormally overexpressed biomarker alkaline phosphatase (ALP) in tumors, enabling in situ activation to induce cell pyroptosis and immunoactivation. Compared to its monophosphate analog (TdVPy-P), the diphosphate probe (TdVPy-PP) demonstrated faster ALP responsiveness and stronger fluorescence output with a fourfold increase in signal-to-noise ratio, enabling specific targeting and aggregation on subcellular organelle membranes (mitochondria and endoplasmic reticulum). This process further boosted localized ROS generation and activated GSDME-mediated pyroptosis, leading to the release of immunogenic antigens that promoted dendritic cell maturation and toxic T cell activation. After complexation with protein, TdVPy-PP can be administered via tail vein injection to target and fluorescently visualize tumor tissue. The growth of primary, distant, and metastatic tumors was significantly suppressed through in situ activated chemodynamic/photodynamic effects combined with systemic immune activation, all while maintaining excellent biocompatibility. This protein-assisted in situ activation strategy offers a promising tool for precise and efficient tumor therapy.
Insights
A novel protein-complexed probe activates cancer cell death and immune responses directly within tumors. This targeted approach suppresses tumor growth and metastasis by leveraging tumor-specific biomarkers for precise theranostics.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Immunotherapy
Background:
- Precision cancer theranostics require in situ synthesis of therapeutics and immune activation within tumor cells.
- Tumor-specific biomarkers can trigger intracellular reactions for targeted therapeutic activation and immune modulation.
Purpose of the Study:
- To design a quenched probe activated by alkaline phosphatase (ALP) for in situ cancer therapy.
- To investigate the probe's ability to induce pyroptosis and immunoactivation for tumor suppression.
Main Methods:
- Developed a protein-complexed diphosphate probe (TdVPy-PP) sensitive to tumor-specific alkaline phosphatase (ALP).
- Evaluated probe responsiveness, fluorescence output, and subcellular localization (mitochondria, endoplasmic reticulum).
- Assessed pyroptosis induction, reactive oxygen species (ROS) generation, and immune cell activation (dendritic cells, T cells) in vitro and in vivo.
- Administered protein-complexed TdVPy-PP via tail vein injection for tumor targeting and visualization.
Main Results:
- TdVPy-PP showed faster ALP response and higher signal-to-noise ratio than TdVPy-P.
- The probe localized to mitochondria and endoplasmic reticulum, enhancing ROS generation and GSDME-mediated pyroptosis.
- In vivo studies demonstrated significant suppression of primary, distant, and metastatic tumor growth.
- Effective dendritic cell maturation and cytotoxic T cell activation were observed, indicating systemic immune enhancement.
Conclusions:
- Protein-assisted in situ activation of TdVPy-PP is a potent strategy for precise cancer theranostics.
- This approach combines chemodynamic/photodynamic effects with systemic immune activation for efficient tumor therapy.
- The developed probe offers a promising tool for targeted cancer treatment with excellent biocompatibility.
