蛋白质笼在生物医学应用中扮演着重要的角色，尤其在肿瘤化疗中。在蛋白质笼中，病毒样颗粒（VLPs）因其在疫苗开发和靶向药物传递方面的潜在应用而受到关注。然而，大多数现有的基于蛋白质的平台技术都深受免疫问题困扰，这些问题可能会限制它们作为药物载体的系统输送效率。在这里，我们展示了使用免疫正交的蛋白质笼顺序和修饰优势环带表位可以规避适应性免疫反应，并使用反复给药实现有效的药物传递。我们基因工程修改了三种不同的乙肝病毒核心蛋白衍生的VLPs，作为多柔比星（DOX）的递送向量。这些工程化的VLPs具有类似的组装特性、颗粒大小和免疫学特性。我们的结果表明，在之前接种了HBV VLPs的小鼠中，这三种RGD-VLPs之间不存在可忽略的抗体交叉反应。此外，多次给予RGD-VLP基的纳米药物（DOX@RGD-VLPs）可有效减少免疫清除并抑制肿瘤生长。因此，本研究可为治疗药物递送提供一种有吸引力的蛋白质笼基础平台。

Protein cages have played a long-standing role in biomedicine applications, especially in tumor chemotherapy. Among protein cages, virus like particles (VLPs) have received attention for their potential applications in vaccine development and targeted drug delivery. However, most of the existing protein-based platform technologies are plagued with immunological problems that may limit their systemic delivery efficiency as drug carriers. Here, we show that using immune-orthogonal protein cages sequentially and modifying the dominant loop epitope can circumvent adaptive immune responses and enable effective drug delivery using repeated dosing. We genetically modified three different hepadnavirus core protein derived VLPs as delivery vectors for doxorubicin (DOX). These engineered VLPs have similar assembly characteristics, particle sizes, and immunological properties. Our results indicated that there was negligible antibody cross-reactivity in either direction between these three RGD-VLPs in mice that were previously immunized against HBc VLPs. Moreover, the sequential administration of multiple RGD-VLP-based nanomedicine (DOX@RGD-VLPs) could effectively reduce immune clearance and inhibited tumor growth. Hence, this study could provide an attractive protein cage-based platform for therapeutic drug delivery.