Wijker Stefan, Deng Linlin, Eisenreich Fabian, Voets Ilja K, Palmans Anja R A
Institute for Complex Molecular Systems, Laboratory of Macromolecular and Organic Chemistry, Eindhoven University of Technology, P.O. Box 513, 5600 MB Eindhoven, The Netherlands.
Laboratory of Self-Organizing Soft Matter, Department of Chemical Engineering and Chemistry, Institute for Complex Molecular Systems, Eindhoven University of Technology, P.O. Box 513, 5600 MB Eindhoven, The Netherlands.
Macromolecules. 2022 Jul 26;55(14):6220-6230. doi: 10.1021/acs.macromol.2c00930. Epub 2022 Jul 13.
Precise control over the folding pathways of polypeptides using a combination of noncovalent and covalent interactions has evolved into a wide range of functional proteins with a perfectly defined 3D conformation. Inspired hereby, we develop a series of amphiphilic copolymers designed to form compact, stable, and structured single-chain polymeric nanoparticles (SCPNs) of defined size, even in competitive conditions. The SCPNs are formed through a combination of noncovalent interactions (hydrophobic and hydrogen-bonding interactions) and covalent intramolecular cross-linking using a light-induced [2 + 2] cycloaddition. By comparing different self-assembly pathways of the nanoparticles, we show that, like for proteins in nature, the order of events matters. When covalent cross-links are formed prior to the folding via hydrophobic and supramolecular interactions, larger particles with less structured interiors are formed. In contrast, when the copolymers first fold via hydrophobic and hydrogen-bonding interactions into compact conformations, followed by covalent cross-links, good control over the size of the SCPNs and microstructure of the hydrophobic interior is achieved. Such a structured SCPN can stabilize the solvatochromic dye benzene-1,3,5-tricarboxamide-Nile Red via molecular recognition for short periods of time in complex media, while showing slow exchange dynamics with the surrounding complex media at longer time scales. The SCPNs show good biocompatibility with cells and can carry cargo into the lysosomal compartments of the cells. Our study highlights the importance of control over the folding pathway in the design of stable SCPNs, which is an important step forward in their application as noncovalent drug or catalyst carriers in biological settings.
通过非共价和共价相互作用的组合对多肽折叠途径进行精确控制，已发展出一系列具有完美定义的三维构象的功能蛋白。受此启发，我们开发了一系列两亲性共聚物，旨在形成尺寸确定的紧凑、稳定且结构化的单链聚合物纳米颗粒（SCPN），即使在竞争条件下也是如此。SCPN是通过非共价相互作用（疏水和氢键相互作用）和使用光诱导[2 + 2]环加成的分子内共价交联的组合形成的。通过比较纳米颗粒的不同自组装途径，我们表明，与自然界中的蛋白质一样，事件的顺序很重要。当通过疏水和超分子相互作用在折叠之前形成共价交联时，会形成内部结构较少的较大颗粒。相反，当共聚物首先通过疏水和氢键相互作用折叠成紧凑构象，然后进行共价交联时，就能很好地控制SCPN的尺寸和疏水内部的微观结构。这种结构化的SCPN可以在复杂介质中通过分子识别在短时间内稳定溶剂致变色染料苯-1,3,5-三甲酰胺-尼罗红，同时在较长时间尺度上与周围复杂介质表现出缓慢的交换动力学。SCPN与细胞具有良好的生物相容性，并且可以将货物运送到细胞的溶酶体区室中。我们的研究强调了在设计稳定的SCPN时控制折叠途径的重要性，这是它们作为生物环境中非共价药物或催化剂载体应用向前迈出的重要一步。
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