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An Implantable Double-Layered Spherical Scaffold Depositing Gene and Cell Agents to Facilitate Collaborative Cancer
Sibei Lei1, Yan Gao1, Kaiyu Wang1
1Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Abstract:
Gene therapies and adoptive cell therapy (ACT) are promising strategies for cancer immunotherapy. Referring to their different mechanisms, the combination of these two might result in a strategy with potential collaborative and compensatory effects. However, it is challenging to combine gene therapies and ACT that work in a proper logical order. Here, we developed a double-layered spherical scaffold (DLS) to codeliver mRNA and T cells and constructed an implantable hydrogel formulation, named the GD-920 scaffold. With a diameter of 7 mm, this scaffold loaded primary T cells in the inner layer and the Bim mRNA nanocomplex in the outer layer. While maintaining their bioactivities, GD-920 released gene and cell payloads in a controllable and sequential manner. The mRNA complex from the outer layer was first released and induced immunogenic tumor cell death. The produced antigens then migrated into the scaffold with dendritic cells, triggering a tumor-specific immune response. Finally, activated T cells released by the inner layer attacked the tumor tissue via massive infiltration. We showed that in situ implantation of the GD-920 scaffold is capable of effectively inhibiting tumor growth and is far more potent than that of control scaffolds containing a single payload. Our results demonstrated the outstanding potential of this DLS in combining gene and cell therapeutic approaches to cancer immunotherapy.
Insights
This study introduces a novel double-layered scaffold (GD-920) for sequential delivery of gene therapy (mRNA) and adoptive cell therapy (ACT) to enhance cancer immunotherapy. The scaffold effectively inhibits tumor growth by orchestrating a targeted immune response.
Area of Science:
- Oncology
- Immunotherapy
- Biomaterials Science
- Gene Therapy
Background:
- Gene therapy and adoptive cell therapy (ACT) are promising cancer immunotherapies.
- Combining gene therapy and ACT presents challenges in achieving synergistic and ordered therapeutic effects.
- Sequential delivery of therapeutic payloads is crucial for optimizing combination strategies.
Purpose of the Study:
- To develop a novel double-layered scaffold (DLS) for the co-delivery of mRNA and T cells.
- To create an implantable hydrogel formulation (GD-920) enabling sequential release of gene and cell payloads.
- To evaluate the efficacy of the GD-920 scaffold in a preclinical cancer model.
Main Methods:
- Development of a 7 mm double-layered spherical scaffold (GD-920).
- Loading of primary T cells into the inner layer and Bim mRNA nanocomplex into the outer layer.
- In situ implantation of the scaffold and assessment of sequential payload release and anti-tumor efficacy.
Main Results:
- The GD-920 scaffold facilitated controllable and sequential release of mRNA and T cells, maintaining their bioactivity.
- Outer layer mRNA release induced immunogenic tumor cell death, attracting dendritic cells and initiating a tumor-specific immune response.
- Inner layer T cell release resulted in massive infiltration and effective inhibition of tumor growth, outperforming single-payload controls.
Conclusions:
- The developed double-layered scaffold (GD-920) enables effective, sequential co-delivery of gene and cell therapies for cancer immunotherapy.
- This approach demonstrates significant potential for synergistic therapeutic effects and enhanced anti-tumor activity.
- The GD-920 scaffold represents a promising platform for advancing combination strategies in cancer treatment.
