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A phase separation-fortified bi-specific adaptor for conditional tumor killing

Science China(Life Sciences) 2024年第7期67卷 1385-1397页

作者： Yuyan Liu Yuting Zhu Weifan Xu Pilong Li State Key Laboratory of Membrane Biology Frontier Research Center for Biological StructureTsinghua University-Peking University Joint Center for Life SciencesSchool of Life SciencesTsinghua UniversityBeijing 100084China

A common approach in therapeutic protein development involves employing synthetic ligands with multivalency,enabling sophisticated control of signal transduction.Leveraging the emerging concept of liquid-liquid phase separation(LLPS)and its ability to organize cell surface receptors into functional compartments,we herein have designed modular ligands with phase-separation modalities to engineer programmable interreceptor communications and precise control of signal pathways,thus inducing the rapid,potent,and specific apoptosis of tumor cells.Despite their simplicity,these“triggers”,named phase-separated Tumor Killers(hereafter referred to as psTK),are sufficient to yield interreceptor clustering of death receptors(represented by DR5)and tumor-associated receptors,with notable features:LLPSmediated robust high-order organization,well-choreographed conditional activation,and broad-spectrum capacity to potently induce apoptosis in tumor cells.The development of novel therapeutic proteins with phase-separation modalities showcases the power of spatially reorganizing signal transduction.This approach facilitates the diversification of cell fate and holds promising potential for targeted therapies against challenging tumors.

关键词： phase separation therapeutic proteins receptor-ligand interactions DR5 tumor apoptosis

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Engineered protein nanodrug as an emerging therapeutic tool

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Nano Research 2022年第6期15卷 5161-5172页

作者： Yuanxin Li Jing Sun Jingjing Li Kai Liu Hongjie Zhang State Key Laboratory of Rare Earth Resource Utilization Changchun Institute of Applied ChemistryChinese Academy of SciencesChangchun 130022China University of Science and Technology of China Hefei 230026China Institute of Organic Chemistry University of UlmAlbert-Einstein-Allee 11Ulm 89081Germany Department of Chemistry Tsinghua UniversityBeijing 100084China

Functional proteins are the most versatile macromolecules.They can be obtained by extraction from natural sources or by genetic engineering technologies.The outstanding selectivity,specificity,binding activity,and biocompatibility endow engineered proteins with outstanding performance for disease therapy.Nevertheless,their stability is dramatically impaired in blood circulation,hindering clinical translations.Thus,many strategies have been developed to improve the stability,efficacy,bioavailability,and productivity of therapeutic proteins for clinical applications.In this review,we summarize the recent progress in the fabrication and application of therapeutic proteins.We first introduce various strategies for improving therapeutic efficacy via bioengineering and nanoassembly.Furthermore,we highlight their diverse applications as growth factors,nanovaccines,antibody-based drugs,bioimaging molecules,and cytokine receptor antagonists.Finally,a summary and perspective for the future development of therapeutic proteins are presented.

关键词： therapeutic proteins nanodrug genetic engineering structural modification therapeutic efficacy

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