Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam.
School of Chemical Engineering, Theranostic Macromolecules Research Center, Sungkyunkwan University, Suwon 16419, Republic of Korea.
Biomaterials. 2019 Mar;195:100-110. doi: 10.1016/j.biomaterials.2018.12.034. Epub 2019 Jan 6.
Lymphoid organs, which are populated by dendritic cells (DCs), are highly specialized tissues and provide an ideal microenvironment for T-cell priming. However, intramuscular or subcutaneous delivery of vaccine to DCs, a subset of antigen-presenting cells, has failed to stimulate optimal immune response for effective vaccination and need for adjuvants to induce immune response. To address this issue, we developed an in situ-forming injectable hybrid hydrogel that spontaneously assemble into microporous network upon subcutaneous administration, which provide a cellular niche to host immune cells, including DCs. In situ-forming injectable hybrid hydrogelators, composed of protein-polymer conjugates, formed a hydrogel depot at the close proximity to the dermis, resulting in a rapid migration of immune cells to the hydrogel boundary and infiltration to the microporous network. The biocompatibility of the watery microporous network allows recruitment of DCs without a DC enhancement factor, which was significantly higher than that of traditional hydrogel releasing chemoattractants, granulocyte-macrophage colony-stimulating factor. Owing to the sustained degradation of microporous hydrogel network, DNA vaccine release can be sustained, and the recruitment of DCs and their homing to lymph node can be modulated. Furthermore, immunization of a vaccine encoding amyloid-β fusion proteinbearing microporous network induced a robust antigen-specific immune response in vivo and strong recall immune response was exhibited due to immunogenic memory. These hybrid hydrogels can be administered in a minimally invasive manner using hypodermic needle, bypassing the need for cytokine or DC enhancement factor and provide niche to host immune cells. These findings highlight the potential of hybrid hydrogels that may serve as a simple, yet multifunctional, platform for DNA vaccine delivery to modulate immune response.
淋巴器官由树突状细胞 (DC) 组成，是高度特化的组织，为 T 细胞的初始激活提供了理想的微环境。然而，将疫苗直接递送至树突状细胞（抗原呈递细胞的一个子集）的肌内或皮下单次接种，未能刺激产生有效的疫苗接种所需的最佳免疫反应，需要佐剂来诱导免疫反应。为了解决这个问题，我们开发了一种原位形成的可注射混合水凝胶，它在皮下单次给药后会自发组装成微孔网络，为宿主免疫细胞（包括树突状细胞）提供细胞龛位。由蛋白-聚合物缀合物组成的原位形成的可注射混合水凝胶形成了一个接近真皮的水凝胶库，导致免疫细胞迅速迁移到水凝胶边界并渗透到微孔网络中。水凝胶的亲水性微孔网络的生物相容性允许 DC 无需 DC 增强因子募集，其募集的 DC 数量明显高于传统水凝胶释放趋化因子粒细胞-巨噬细胞集落刺激因子。由于微孔水凝胶网络的持续降解，DNA 疫苗的释放可以持续，并且可以调节 DC 的募集及其向淋巴结的归巢。此外，在体内用编码带有微孔网络的淀粉样β融合蛋白的疫苗免疫，可诱导出强大的抗原特异性免疫反应，由于免疫记忆，可引发强烈的回忆性免疫反应。这些混合水凝胶可以通过皮下注射进行微创给药，无需细胞因子或 DC 增强因子，并且为宿主免疫细胞提供了一个龛位。这些发现强调了混合水凝胶的潜力，它们可能成为一种简单而多功能的 DNA 疫苗传递平台，用于调节免疫反应。
