乙型肝炎核心蛋白病毒样颗粒（HBc VLPs）由于其优异的稳定性和易于大规模生产而作为药物递送载体引起了广泛关注。在目前的工作中，我们报告了用于抗癌药物递送的 HBc 颗粒独特的热触发加载和谷胱甘肽响应释放特性。通过 HBc 颗粒衣壳的可逆温度依赖性孔门控，通过简单地将 DOX 与 HBc 在 70 °C 下孵育 90 分钟，约 4248 个多柔比星 (DOX) 成功封装在单个纳米颗粒的纳米笼内，HBc 回收率高达 83.2% . 新策略明显优于拆卸-重组方法，后者只能在 52.3% HBc 回收率下产生 3556 DOX 负载。通过分子动力学模拟分析HBc中的热敏药物进入通道，确定G113、G117和R127为不利于DOX进入但对温度敏感的关键氨基酸残基。特别地，ΔR127的G结合在高温下变得更高，R127的突变将是使药物进入热力学更容易的首选。由于连接 HBc 亚基的大量二硫键，载有 DOX 的 HBc 颗粒表现出内在的谷胱甘肽 (GSH) 响应性，可在肿瘤部位有效控制释放。为了进一步提高药物的肿瘤靶向作用，Cyclo(Arg-Gly-Asp-d-Tyr-Lys) 肽通过 PEG 接头与 HBc 表面结合。所制备的基于 HBc 的抗癌药物显示出显着改善的稳定性、肿瘤特异性和体内活性。对携带 MCF7 的 Balb/c-nu 小鼠的抗癌活性。总的来说，我们的工作表明 HBc VLP 可以成为理想的药物载体，以满足智能加载和“按需”释放治疗剂的要求，以实现有效的癌症治疗，同时将副作用降到最低。

"点击查看英文标题和摘要"

Hepatitis B core protein virus-like particles (HBc VLPs) have attracted wide attentions using as drug delivery vehicles, due to its excellent stability and easy in large scale production. Here in the present work, we report unique thermal-triggered loading and glutathione-responsive releasing property of the HBc particles for anticancer drug delivery. Through reversible temperature-dependent hole gating of the HBc particle capsid, about 4248 doxorubicin (DOX) were successfully encapsulated inside nanocage of a single nanoparticle at high HBc recovery of 83.2%, by simply incubating the DOX with HBc at 70 °C for 90 min. The new strategy was significantly superior to the disassembly-reassembly methods, which can only yield 3556 DOX loading at 52.3% HBc recovery. The thermal-sensitive drug entry channel in HBc was analyzed by molecular dynamic simulations, and the G113, G117 and R127 were identified as the key amino acid residues that are not conducive to the entrance of DOX but sensitive to temperature. Especially, the ΔGbind of R127 become even higher at high temperature, mutation of the R127 would be the first choice to make the drug entry thermodynamically easier. Due to plenty of disulfide bonds linking the HBc subunits, the HBc particles loaded with DOX exhibited intrinsic glutathione (GSH) responsivity for efficient controlled release in tumor sites. To further increase the tumor-targeting effect of the drug, Cyclo(Arg-Gly-Asp-d-Tyr-Lys) peptide was conjugated to the surface of HBc through a PEG linker. The prepared HBc-based anticancer drug showed significantly improved stability, tumor specificity, and in vivo anticancer activity on MCF7-bearing Balb/c-nu mice. Overall, our work demonstrated that the HBc VLPs can be an ideal drug carrier to fulfill requirement of the intelligent loading and “on demand” release of the therapeutic agents for efficient cancer therapy with minimal adverse effects.