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Metal Ion Assisted Interface Re-engineering of Ferritin Protein Nanocage for Enhanced Biofunctions and Cancer Therapy

机译：铁离子蛋白纳米笼金属离子辅助界面再造以增强生物功能和癌症治疗。

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The bottom-up self-assembly of protein subunits into supramolecular nanoarchitectures is ubiquitously exploited to recapitulate and expand features of natural proteins to advance nanoscience in medicine. Various chemical and biological re-engineering approaches are available to render given proteins diverse functions. They are, unfortunately, susceptible of compromising protein integrity and stability after extensive modifications. In this study, we introduce a new protein re-engineering method, metal ion assisted interface re-engineering (MAIR), to serve as a robust and universal strategy to extend functions of self-assembly proteins with boosted structural features to advance its diverse biomedical applications. In particular, the MAIR strategy was applied to a widely used natural protein, ferritin, as a model protein to coordinate with copper ions in its mutagenic artificial metal binding domain. Structure directed rational protein mutagenesis was carried out at the C2 interface amino acid residues of the ferritin subunit for metal ion coordination site optimization. Copper binding at the artificial binding pocket was highly specific over the other divalent ions present in physiological fluids, and the structurally embedded copper ion in turn strengthened the overall protein integrity and stability. In the presence of isotopic copper-64, the interface re-engineered ferritin worked as a chelator-free molecular nanoprobe with extraordinarily high specific activity to allow PET imaging of tumors in live animals. We also found that the re-engineered ferritin coordinating with copper ions demonstrates high drug loading capacity of a widely used anti-cancer agent, doxorubicin (DOX), to achieve significant drug retention at the tumor site and enhance tumor regression for improved anti-cancer effects. The MAIR approach, thus, exploited the copper ion to facilitate mutant ferritin derivatives efficient one-step labeling for simultaneous molecular imaging and drug delivery. The reported interface re-engineering strategy provides an unparalleled opportunity to expand protein biofunctions to serve as a new theranostic agent in cancer research.
机译：蛋白亚基自下而上的自组装成为超分子纳米结构被广泛利用以概括和扩展天然蛋白的功能，从而推进医学的纳米科学。可以使用各种化学和生物再造方法来使给定的蛋白质具有多种功能。不幸的是，经过大量修饰后，它们容易损害蛋白质的完整性和稳定性。在这项研究中，我们介绍了一种新的蛋白质再造方法，即金属离子辅助界面再造（MAIR），作为一种强大且通用的策略来扩展具有增强结构特征的自组装蛋白质的功能，从而促进其多样化的生物医学应用程序。尤其是，MAIR策略已应用于广泛使用的天然蛋白铁蛋白，作为模型蛋白，可与诱变的人工金属结合域中的铜离子配合。在铁蛋白亚基的C2界面氨基酸残基上进行结构定向的理性诱变，以优化金属离子配位位点。人工结合口袋处的铜结合对生理液中存在的其他二价离子具有高度特异性，结构上嵌入的铜离子反过来又增强了整体蛋白质的完整性和稳定性。在存在同位素铜64的情况下，重新设计的界面铁蛋白可作为无螯合剂的分子纳米探针，具有超高的比活度，可对活体动物的肿瘤进行PET成像。我们还发现，与铜离子配合使用的重新设计的铁蛋白证明了广泛使用的抗癌药阿霉素（DOX）的高载药量，可在肿瘤部位实现显着的药物保留并增强肿瘤消退，从而改善抗癌能力效果。因此，MAIR方法利用铜离子来促进突变型铁蛋白衍生物的高效一步标记，以同时进行分子成像和药物递送。报道的界面再造策略为扩展蛋白质生物功能提供了无与伦比的机会，可以用作癌症研究中的新型治疗药物。

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