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Multifunctional nanozymes for sonodynamic-enhanced immune checkpoint blockade therapy by inactivating PI3K/AKT signal
Mei Wen1, Pu Qiu1, Jialan Meng2
1State Key Laboratory of Advanced Fiber Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, China.
Abstract:
Insufficient activation efficacy and tumor immunosuppressive microenvironments hinder the infiltration of cytotoxic T lymphocytes (CTLs) for effective immunotherapy. Herein, the pH-selective multienzyme-mimetic nanozymes have been developed based on Pd-hemoporfin (Pd0/Pd2+‒H) nanoagents for tumor sono-immunotherapy via the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway inactivation. The Pd0/Pd2+‒H is capable of catalase-mimetic, peroxidase-mimetic, and sonodynamic effects, creating an O2-rich environment and elevating the reactive oxygen species (ROS) levels. The elevated ROS levels down-regulate the expression of PI3K and p-AKT on both gene and protein levels, leading to PI3K/AKT pathway inactivation. Subsequently, the augmented immunogenic cell death effectively recruits dendritic cells, presents tumor-associated antigens, and activates antitumor T-cell immunity. As a result, the combination of Pd0/Pd2+‒H and anti-programmed cell death protein ligand 1 results in growth restraints of primary and precaution of tumor metastases. This work offers insights into developing multienzyme-mimetic nanozymes in signaling pathway regulation and antitumor strategy.
Insights
New nanozymes enhance cancer immunotherapy by inactivating the PI3K/AKT pathway, boosting T-cell responses and reducing tumor growth. This approach shows promise for overcoming tumor immunosuppression and preventing metastasis.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Immunology
- Oncology
Background:
- Cancer immunotherapy faces challenges due to insufficient T-cell activation and immunosuppressive tumor microenvironments.
- Targeting key signaling pathways like PI3K/AKT is crucial for enhancing anti-tumor immune responses.
Purpose of the Study:
- To develop pH-selective multienzyme-mimetic nanozymes for tumor sono-immunotherapy.
- To investigate the inactivation of the PI3K/AKT pathway using Pd-hemoporfin (Pd0/Pd2+‒H) nanoagents.
- To evaluate the combined efficacy of nanozymes and anti-PD-L1 therapy in controlling tumor growth and metastasis.
Main Methods:
- Synthesis of Pd-hemoporfin (Pd0/Pd2+‒H) nanoagents with catalase-mimetic, peroxidase-mimetic, and sonodynamic properties.
- Evaluation of nanoagent-induced O2 generation and reactive oxygen species (ROS) elevation.
- Assessment of PI3K/AKT pathway inhibition at both gene and protein levels.
- Analysis of immunogenic cell death, dendritic cell recruitment, and T-cell activation.
- In vivo studies combining nanoagents with anti-PD-L1 therapy to assess tumor growth restraint and metastasis prevention.
Main Results:
- Pd0/Pd2+‒H nanoagents successfully created an oxygen-rich environment and increased ROS levels.
- Elevated ROS down-regulated PI3K and p-AKT expression, leading to PI3K/AKT pathway inactivation.
- Enhanced immunogenic cell death was observed, promoting dendritic cell recruitment and T-cell activation.
- Combined treatment with Pd0/Pd2+‒H and anti-PD-L1 significantly inhibited primary tumor growth and prevented metastases.
Conclusions:
- pH-selective multienzyme-mimetic nanozymes effectively promote sono-immunotherapy by targeting the PI3K/AKT pathway.
- This strategy enhances anti-tumor immunity and offers a potential therapeutic approach for cancer treatment.
- The findings provide insights into utilizing nanozymes for signaling pathway regulation and developing novel antitumor strategies.
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