Turing milk into pro-apoptotic oral nanotherapeutic: De novo bionic chiral-peptide supramolecule for cancer targeted and immunological therapy.
Turing milk into pro-apoptotic oral nanotherapeutic: De novo bionic chiral-peptide supramolecule for cancer targeted and immunological therapy.
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作者：
He W;Zhang Z;Yang W;Zheng X;You W;Yao Y;Yan J;Liu W
生物分子中的手性在我们的世界中无处不在，但由手性肽构建的口服纳米药物却极为罕见，主要是因为纳米制造技术不成熟和手性纳米结构的生物利用度不足。方法：为了实现手性肽的口服给药，突破其在细胞内空间的禁区，本文通过有机硫醇d肽和Au3+参与的手性肽Au(I)无限共价聚合物（DPAICP）的水基生长方法，以及一种可行的ME伪装技术，开发了一种用乳源性细胞外囊泡（ME）膜伪装的手性肽超分子（DPAICP）。结果：DPAICP@ME具有良好的药理性能，在胃肠道吸收和血液循环中保持稳定，经口服给药后表现出满意的肿瘤蓄积。在B16F10同种移植物恶性黑色素瘤模型、LLC Lewis肺癌原位移植模型和患者源性原位异种移植（PDOX）小鼠结肠癌模型中，口服DPAICP@ME在体内发挥了其预定的修复p53信号通路的作用。此外，口服DPAICP@ME通过进一步激活t细胞，增强了Anti-PD1免疫治疗的作用。结论：仿生手性肽超分子的重新设计为构建可口服的仿生手性肽衍生纳米结构提供了一种可行的策略，并可能促进包括癌症在内的更广泛疾病的手性纳米药物的发现。
Chirality in biomolecules is ubiquitous in our world, but oral nanomedicines constructed from chiral peptides are extremely rare, principally because of the immature nanofabrication and inadequate bioavailability of chiral nanostructures. Methods: To realize the oral administration of chiral peptides and break through their forbidden zone in intracellular space, a chiral-peptide supramolecular (DPAICP) camouflaging with the membrane from milk-derived extracellular vesicles (ME) was developed herein through an aqueous-based growth method of chiral peptide Au(I) infinite covalent polymer (DPAICP) involving in organothiol D-peptides and Au3+, and a feasible camouflage technology using ME. Results: DPAICP@ME possessed favorable pharmaceutical properties to remain stable during the gastrointestinal absorption and blood circulation, and showed the satisfactory tumor accumulation through oral medication. Expectedly, oral DPAICP@ME played its predetermined role in vivo to restore p53 signaling pathway for cancer therapy in B16F10 homograft malignant melanoma model, LLC Lewis orthotopic transplantation model of lung cancer and patient-derived orthotopic xenograft (PDOX) mice model of colon cancer. Moreover, oral DPAICP@ME augmented the action of immunotherapy by Anti-PD1 through the further T-cell activation. Conclusion: The de novo design of the bionic chiral-peptide supramolecule provides a practicable strategy for the construction of biomimetic chiral peptide-derived nanostructures that can be taken orally, and likely boosts chiral nanomedicine discovery efforts for a wider range of diseases including cancer.
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