Polyamine-Depleting Hydrogen-Bond Organic Frameworks Unleash Dendritic Cell and T Cell Vigor for Targeted
Yongchun Pan1, Fei Zeng1, Xiaowei Luan1
1College of Engineering and Applied Sciences, State Key Laboratory of Analytical Chemistry for Life Science, National Laboratory of Solid State Microstructures, Nanjing University, Nanjing, 210023, China.
Abstract:
Polyamines have tantalized cancer researchers as a potential means to rein in the rampant growth of cancer cells. However, clinical trials in recent decades have disappointed in delivering notable progress. Herein, a microfluidic-assisted synthetic hydrogen-bond organic framework (HOF) as a polyamine-depleting nanoplatforms designed to unleash the vigor of both dendritic cells (DCs) and T cells for precision cancer immunotherapy is reported. Upon internalization by tumor cells, the loaded plasma amine oxidase (PAO) in HOF efficiently depletes polyamines, remolding the tumor microenvironment and alleviating T-cell immunosuppression. This process also generates acrolein and H2O2, triggering CRISPR-assisted neoantigen generation. Specifically, Acrolein induces carbonyl stress, increasing mutational burdens. Simultaneously, HOF leverages the energy from the bis[2,4,5-trichloro-6-(pentyloxycarbonyl)phenyl] oxalate (CPPO)-H2O2 reaction for CRET-triggered singlet oxygen production, leading to thioether bond cleavage and release CRISPR-Cas9. Once released, CRISPR-Cas9 knocks out the DNA mismatch repair (MMR)-related MLH1 gene, further elevating mutational burdens and generating neoantigens, ideal targets for DCs. This dual-action strategy not only corrects T-cell immunosuppression but also enhances DC efficacy, presenting a powerful approach for tumor immunotherapy.
Insights
This study introduces a novel nanoplatform that depletes polyamines in cancer cells, enhancing immune responses. This approach boosts dendritic cell and T-cell activity for effective cancer immunotherapy.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Immunotherapy
Background:
- Polyamines are implicated in cancer cell proliferation, but clinical trials targeting them have yielded limited success.
- Existing strategies for cancer immunotherapy face challenges with T-cell immunosuppression and suboptimal dendritic cell (DC) activation.
Purpose of the Study:
- To develop a microfluidic-assisted synthetic hydrogen-bond organic framework (HOF) nanoplatform for polyamine depletion.
- To enhance cancer immunotherapy by reactivating dendritic cells (DCs) and T cells.
Main Methods:
- Utilized a HOF nanoplatform loaded with plasma amine oxidase (PAO) to deplete tumor cell polyamines.
- Generated acrolein and hydrogen peroxide (H₂O₂) to induce carbonyl stress and increase mutational burden.
- Employed a chemiexcitation reaction for CRET-triggered singlet oxygen production to release CRISPR-Cas9.
- CRISPR-Cas9 targeted the MLH1 gene to further elevate mutational burden and neoantigen generation.
Main Results:
- The nanoplatform successfully depleted polyamines, remolded the tumor microenvironment, and alleviated T-cell immunosuppression.
- Acrolein generation increased tumor mutational burden.
- CRISPR-Cas9 mediated gene editing of MLH1 enhanced neoantigen presentation, boosting DC efficacy.
- The dual-action strategy demonstrated a potent approach for tumor immunotherapy.
Conclusions:
- The developed polyamine-depleting HOF nanoplatform offers a promising strategy for precision cancer immunotherapy.
- This approach effectively enhances both DC and T-cell functions by modulating the tumor microenvironment and increasing neoantigen load.
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