Bortezomib (BTZ) is a first-in-class boronate proteasome inhibitor used for cancer therapy, but its therapeutic efficacy is usually inhibited by dietary polyphenols due to boronate-catechol complexation. Benefiting from such dynamic covalent chemistry, herein we describe a novel class of supramolecular nanomedicines by rationally converting natural polyphenols from foe to friend through polyphenol-mediated BTZ assembly strategy. The simple conjugation of BTZ to catechol-containing natural polyphenols via boronate ester bond allows the facile formation of dynamic drug amphiphiles, with pH-dependent assembly/disassembly behaviors under different physiological conditions. Ferric ion was also incorporated into the supramolecular system via metal-phenolic coordination interaction to both introduce bioimaging function and facilitate stability of the supramolecular nanomedicines. Our investigation revealed that the supramolecular nanomedicine consisting of natural polyphenol, BTZ and ferric ion dramatically induced apoptosis on cancer cells and suppressed tumor growth in both subcutaneous and bone tumor models with limited adverse effects. Such natural polyphenol-mediated small drug assembly strategy enables the robust fabrication of supramolecular nanomedicines for efficient delivery and controlled release of BTZ in targeted tumor sites, which could be further employed in other types of boronic acid-containing supramolecular therapeutics toward a wide range of diseases.

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仇敌：天然多酚和硼替佐米组成的超分子纳米药物

硼替佐米（BTZ）是用于癌症治疗的一流的硼酸盐蛋白酶体抑制剂，但由于硼酸盐-邻苯二酚的络合作用，其饮食功效通常会被饮食中的多酚抑制。受益于这种动态共价化学，本文中我们通过通过多酚介导的BTZ组装策略合理地将天然多酚从仇敌转化为友敌来描述一类新型的超分子纳米药物。BTZ通过硼酸酯键与含邻苯二酚的天然多酚的简单缀合可轻松形成动态药物两亲物，并在不同的生理条件下具有pH依赖的组装/拆卸行为。还通过金属-酚配位相互作用将铁离子掺入超分子系统中，以引入生物成像功能并促进超分子纳米药物的稳定性。我们的研究表明，由天然多酚，BTZ和铁离子组成的超分子纳米药物在皮下和骨肿瘤模型中均能显着诱导癌细胞凋亡并抑制肿瘤生长，且不良反应有限。这种天然的多酚介导的小分子药物组装策略能够可靠地制造超分子纳米药物，以便在目标肿瘤部位有效释放和控制BTZ的释放，并可进一步用于其他类型的含硼酸的超分子治疗剂，以治疗多种疾病。我们的研究表明，由天然多酚，BTZ和铁离子组成的超分子纳米药物在皮下和骨肿瘤模型中均能显着诱导癌细胞凋亡并抑制肿瘤生长，且不良反应有限。这种天然的多酚介导的小药物组装策略能够可靠地制造超分子纳米药物，以在目标肿瘤部位有效释放和控制BTZ的释放，并可进一步用于其他类型的含硼酸的超分子治疗剂，以治疗多种疾病。我们的研究表明，由天然多酚，BTZ和铁离子组成的超分子纳米药物在皮下和骨肿瘤模型中均能显着诱导癌细胞凋亡并抑制肿瘤生长，且不良反应有限。这种天然的多酚介导的小分子药物组装策略能够可靠地制造超分子纳米药物，以便在目标肿瘤部位有效释放和控制BTZ的释放，并可进一步用于其他类型的含硼酸的超分子治疗剂，以治疗多种疾病。