Abstract：
Remarkable progress has been made in tumour immunotherapy in recent decades. However, the clinical outcomes of therapeutic interventions remain unpredictable, largely because of inefficient immune responses. To address this challenge and optimise immune stimulation, we present a novel administration route for enhancing the bioavailability of immunotherapeutic drugs. Our approach involves the development of an oral tumour vaccine utilising virus-like particles derived from the Hepatitis B virus core (HBc) antigen. The external surfaces of these particles are engineered to display the model tumour antigen OVA, whereas the interiors are loaded with cytosine phosphoguanosine oligodeoxynucleotide (CpG ODN), resulting in a construct called CpG@OVAHBc with enhanced antigenicity and immune response. For oral delivery, CpG@OVAHBc is encapsulated in a crosslinked dextran hydrogel called CpG@OVAHBc@Dex. The external hydrogel shield safeguards the biomimetic virus particles from degradation by gastric acid and proteases. Upon exposure to intestinal flora, the hydrogel disintegrates, releasing CpG@OVAHBc at the intestinal mucosal site. Owing to its virus-like structure, CpG@OVAHBc exhibits enhanced adhesion to the mucosal surface, facilitating uptake by microfold cells (M cells) and subsequent transmission to antigen-presenting cells. The enzyme-triggered release of this oral hydrogel ensures the integrity of the tumour vaccine within the digestive tract, allowing targeted release and significantly improving bioavailability. Beyond its efficacy, this oral hydrogel vaccine streamlines drug administration, alleviates patient discomfort, and enhances treatment compliance without the need for specialised injection methods. Consequently, our approach expands the horizons of vaccine development in the field of oral drug administration.
摘要：
近几十年来，肿瘤免疫治疗取得了显著进展。然而,治疗干预的临床结果仍然不可预测，很大程度上是因为低效的免疫反应。为了应对这一挑战并优化免疫刺激，我们提出了一种提高免疫治疗药物生物利用度的新给药途径。我们的方法涉及利用源自乙型肝炎病毒核心（HBc）抗原的病毒样颗粒开发口腔肿瘤疫苗。这些颗粒的外表面经过工程改造以显示模型肿瘤抗原OVA，而内部装有胞嘧啶磷酸鸟苷寡脱氧核苷酸（CpGODN），产生称为CpG@OVAHBc的构建体，具有增强的抗原性和免疫应答。对于口服递送，CpG@OVAHBc封装在称为CpG@OVAHBc@Dex的交联葡聚糖水凝胶中。外部水凝胶屏蔽保护仿生病毒颗粒免受胃酸和蛋白酶的降解。暴露于肠道菌群后,水凝胶崩解，在肠粘膜部位释放CpG@OVAHBc。由于它的病毒样结构，CpG@OVAHBc表现出对粘膜表面的粘附增强，促进微折叠细胞（M细胞）的摄取和随后传递给抗原呈递细胞。这种口服水凝胶的酶触发释放确保了肿瘤疫苗在消化道内的完整性，允许靶向释放并显着提高生物利用度。除了它的功效，这种口服水凝胶疫苗简化了药物管理，减轻患者的不适，并提高治疗依从性，而不需要专门的注射方法。因此,我们的方法拓展了口服药物领域疫苗开发的视野.
