Ministry of Education Key Laboratory of Functional Polymer Materials, State Key Laboratory of Medicinal Chemical Biology, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China.
State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin 300071, China.
J Am Chem Soc. 2022 Apr 20;144(15):6907-6917. doi: 10.1021/jacs.2c01323. Epub 2022 Apr 7.
Enzyme-regulated in situ self-assembly of peptides represents one versatile strategy in the creation of theranostic agents, which, however, is limited by the strong dependence on enzyme overexpression. Herein, we reported the self-amplifying assembly of peptides precisely in macrophages associated with enzyme expression for improving the anti-inflammatory efficacy of conventional drugs. The self-amplifying assembling system was created via coassembling an enzyme-responsive peptide with its derivative functionalized with a protein ligand. Reduction of the peptides by the enzyme NAD(P)H quinone dehydrogenase 1 (NQO1) led to the formation of nanofibers with high affinity to the protein, thereby facilitating NQO1 expression. The improved NQO1 level conversely promoted the assembly of the peptides into nanofibers, thus establishing an amplifying relationship between the peptide assembly and the NQO1 expression in macrophages. Utilization of the amplifying assembling system as vehicles for drug dexamethasone allowed for its passive targeting delivery to acute injured lungs. Both in vitro and in vivo studies confirmed the capability of the self-amplifying assembling system to enhance the anti-inflammatory efficacy of dexamethasone via simultaneous alleviation of the reactive oxygen species side effect and downregulation of proinflammatory cytokines. Our findings demonstrate the manipulation of the assembly of peptides in living cells with a regular enzyme level via a self-amplification process, thus providing a unique strategy for the creation of supramolecular theranostic agents in living cells.
酶调控的肽原位自组装代表了一种用于构建治疗药物的多功能策略，然而，该策略受到酶过表达的强烈依赖限制。在此，我们报道了肽在与酶表达相关的巨噬细胞中精确的自扩增组装，以提高常规药物的抗炎疗效。自扩增组装系统是通过共组装一个酶响应肽及其衍生的与蛋白质配体功能化的肽来创建的。该酶 NAD(P)H 醌氧化还原酶 1 (NQO1) 将肽还原为具有与蛋白质高亲和力的纳米纤维，从而促进 NQO1 表达。相反，提高的 NQO1 水平促进了肽组装成纳米纤维，从而在巨噬细胞中建立了肽组装和 NQO1 表达之间的放大关系。将该扩增组装系统用作药物地塞米松的载体，可使其被动靶向递送至急性损伤的肺部。体外和体内研究均证实，自扩增组装系统能够通过同时缓解活性氧副作用和下调促炎细胞因子来增强地塞米松的抗炎疗效。我们的研究结果表明，可以通过自扩增过程在活细胞中以常规酶水平来操纵肽的组装，从而为在活细胞中构建超分子治疗药物提供了一种独特的策略。
