Introduction

Biomaterials that enable in situ recruitment and modulation of immune cells have demonstrated tremendous promise for developing potent cancer immunotherapy such as therapeutic cancer vaccine. One challenge related to biomaterial scaffold-based cancer vaccines is the development of macroporous materials that are biocompatible and stable, enable controlled release of chemokines to actively recruit a large number of dendritic cells (DCs), contain macropores that are large enough to home the recruited DCs, and support the survival and proliferation of DCs

Methods

Bio-adhesive macroporous gelatin hydrogels were synthesized and characterized for mechanical properties, porous structure, and adhesion towards tissues. The recruitment of immune cells including DCs to chemokine-loaded bioadhesive macroporous gels was analyzed. The ability of gels loaded with granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor extracellular vesicles (EVs) to elicit tumor-specific CD8⁺ T cell responses was also analyzed.

Results

Here we develop a bioadhesive macroporous hydrogel that can strongly adhere to tissues, contain macropores that are large enough to home immune cells, are mechanically tough, and enable controlled release of chemokines to recruit and modulate immune cells in situ. The macroporous hydrogel is composed of a double crosslinked network of gelatin and polyacrylic acid, and the macropores are introduced via cryo-polymerization. By incorporating GM-CSF and tumor EVs into the macroporous hydrogel, a high number of DCs can be recruited in situ to process and present EV-encased antigens. These tumor antigen-presenting DCs can then traffic to lymphatic tissues to prime antigen-specific CD8⁺ T cells.

Conclusion

This bioadhesive macroporous hydrogel system provides a new platform for in situ recruitment and modulation of DCs and the development of enhanced immunotherapies including tumor EV vaccines. We also envision the promise of this material system for drug delivery, tissue regeneration, long-term immunosuppression, and many other applications.

中文翻译：

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用于树突状细胞原位招募和调节的生物粘附大孔水凝胶

介绍

能够原位招募和调节免疫细胞的生物材料已在开发有效的癌症免疫疗法（例如治疗性癌症疫苗）方面展现出巨大的前景。与基于生物材料支架的癌症疫苗相关的一项挑战是开发具有生物相容性和稳定性的大孔材料，能够控制释放趋化因子以主动招募大量树突状细胞（DC），并且含有足够大的大孔以容纳招募的树突状细胞。 DC，并支持 DC 的生存和增殖

方法

合成了生物粘附性大孔明胶水凝胶，并对其机械性能、多孔结构和组织粘附性进行了表征。分析了免疫细胞（包括 DC）向负载趋化因子的生物粘附大孔凝胶的募集情况。还分析了负载粒细胞巨噬细胞集落刺激因子 (GM-CSF) 和肿瘤细胞外囊泡 (EV) 的凝胶引发肿瘤特异性 CD8 ⁺ T 细胞反应的能力。

结果

在这里，我们开发了一种生物粘附性大孔水凝胶，它可以牢固地粘附在组织上，含有足够大的大孔以容纳免疫细胞，机械坚固，并且能够控制趋化因子的释放，以在原位招募和调节免疫细胞。大孔水凝胶由明胶和聚丙烯酸的双交联网络组成，通过冷冻聚合引入大孔。通过将 GM-CSF 和肿瘤 EV 合并到大孔水凝胶中，可以原位招募大量 DC 来处理和呈递 EV 包裹的抗原。然后，这些肿瘤抗原呈递 DC 可以运输到淋巴组织，以启动抗原特异性 CD8 ⁺ T 细胞。

结论

这种生物粘附性大孔水凝胶系统为 DC 的原位招募和调节以及包括肿瘤 EV 疫苗在内的增强免疫疗法的开发提供了一个新平台。我们还展望了这种材料系统在药物输送、组织再生、长期免疫抑制和许多其他应用中的前景。