Institute of Bioengineering, School of Life Sciences and School of Engineering, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
Biomaterials. 2012 Sep;33(26):6211-9. doi: 10.1016/j.biomaterials.2012.04.060. Epub 2012 Jun 1.
While current subunit vaccines successfully induce humoral immune responses, a need exists for vaccine strategies to elicit strong cell-mediated immunity to address diseases such as cancer and chronic viral infection. Polymersomes are stable vesicles composed of self-assembling block copolymers with tunable degradation properties allowing delivery of both hydrophilic (within vesicle interior) or hydrophobic (within vesicle membrane) payload molecules. Here we apply oxidation-sensitive nanoscale polymersomes for both antigen and adjuvant delivery to dendritic cell (DC) endosomes. Calcein-loaded polymersomes were observed to release their payload initially in multiple DC endosomal compartments and subsequently within the cytosol. With either the Toll-like receptor agonists gardiquimod or R848 as payloads within the polymersomes, release resulted in DC activation, as indicated by induction of inflammatory cytokine expression and upregulation of DC maturation surface markers: for example, the ability of gardiquimod to induce IL-6 and IL-12 cytokine expression by DCs was enhanced 10-fold when loaded within polymersomes. With the model antigen ovalbumin as a payload, release resulted in CD8(+) T cell cross-priming by promoting protein antigen cross-presentation through MHC I, as indicated by activation of OT-I CD8(+) T cells. Our results demonstrate that oxidation-sensitive polymersomes can function as a vaccine delivery platform for inducing cell-mediated antigen-specific immune responses.
虽然当前的亚单位疫苗成功地诱导了体液免疫反应，但仍需要疫苗策略来引发强烈的细胞介导免疫，以解决癌症和慢性病毒感染等疾病。聚合物囊泡是由自组装嵌段共聚物组成的稳定囊泡，具有可调节的降解特性，允许亲水（囊泡内部）或疏水（囊泡膜内）有效负载分子的递呈。在这里，我们将氧化敏感的纳米级聚合物囊泡应用于树突状细胞 (DC) 内体中的抗原和佐剂递呈。负载 calcein 的聚合物囊泡最初被观察到在多个 DC 内体隔室中释放其有效负载，随后在细胞质内释放。无论是将 Toll 样受体激动剂 gardiquimod 还是 R848 作为聚合物囊泡内的有效负载，释放都会导致 DC 激活，这表现为炎症细胞因子表达和 DC 成熟表面标志物的上调：例如，当 gardiquimod 负载在聚合物囊泡内时，其诱导 DC 产生 IL-6 和 IL-12 细胞因子的能力增强了 10 倍。对于模型抗原卵清蛋白作为有效负载，释放通过 MHC I 促进蛋白抗原交叉呈递，从而导致 CD8(+)T 细胞交叉呈递，这表明 OT-I CD8(+)T 细胞被激活。我们的结果表明，氧化敏感的聚合物囊泡可以作为一种疫苗递送平台，用于诱导细胞介导的抗原特异性免疫反应。
