Noninvasive ultrasound is more convenient and easily accessible for controlled drug delivery of polymeric nanoparticles than many other stimuli. However, controlled ultrasound responsiveness is rather challenging as the mechanism is still unclear. In this article, we disclose the origin and the key regulating factors of ultrasound responsiveness of block copolymer nanoparticles such as simple vesicles, framboidal vesicles, lamellae, beads-like micelles and complex micelles that are self-assembled from a range of poly(ethylene oxide)-b-polymethacrylates based model copolymers. We discover that the intrinsic ultrasound responsiveness of block copolymer nanoparticles thermodynamically originates from their metastable states, and its expression kinetically relates to the mobility of the hydrophobic segments of block copolymers. Specifically, the self-assembly temperature (T_s) that has been usually considered as a less important factor in most of macromolecular self-assembly systems, and the solvents for the selfassembly are two dominant regulating factors of the ultrasound responsiveness because they determine the thermodynamic state (metastable or stable) of nanoparticles. For example, simple vesicles with good or excellent ultrasound responsiveness can be prepared in THF/water when the T_s is around or slightly below the glass transition temperature (T_g) of the hydrophobic segment of the block copolymer because the combination of this solvent with this T_s facilitates the formation of metastable vesicles. By contrast, thermodynamically stable solid nanoparticles such as spherical micelles and lamellae (mainly formed in DMF/water) are not sensitive to ultrasound at all, neither are the vesicles in THF/water at stable states when the T_s is highly above T_g. In addition, we unravel that the responsive rate is highly dependent on the sonication temperature (T_u), i.e., the higher the T_u, the faster the rate. Overall, the above important findings provide us with a fresh insight into how to design ultrasound-responsive nanoparticles and may open new avenues for synthesizing translational noninvasively responsive drug carriers.

中文翻译：

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嵌段共聚物纳米粒子超声响应性的起源与调控

与许多其他刺激相比，非侵入性超声对于聚合物纳米颗粒的受控药物输送更为方便和容易获得。但是，由于机制尚不清楚，因此可控的超声反应性颇具挑战性。在本文中，我们揭示了嵌段共聚物纳米粒子的超声响应性的起源和关键调节因素，例如，它们是由一系列聚环氧乙烷自行组装而成的简单囊泡，卵形囊泡，片状，珠状胶束和复杂胶束）-b-基于聚甲基丙烯酸酯的模型共聚物。我们发现，嵌段共聚物纳米粒子的内在超声响应能力是热力学上起源于其亚稳态的，其表达在动力学上与嵌段共聚物的疏水链段的迁移率有关。具体来说，在大多数高分子自组装系统中通常被认为次要因素的自组装温度（T _s）和用于自组装的溶剂是超声响应性的两个主要调节因素，因为它们决定了热力学。纳米粒子的状态（可稳定或稳定）。例如，当T _{s达到一定值}时，可以在THF /水中制备具有良好或优异的超声响应能力的简单囊泡_。该温度约为或略低于嵌段共聚物的疏水链段的玻璃化转变温度（T _g），因为该溶剂与该T _s的组合促进了亚稳囊泡的形成。相比之下，热力学稳定的固体纳米颗粒（例如球形胶束和薄片）（主要在DMF /水中形成）对超声波完全不敏感，当T _s高度高于T _g时，在THF /水中的囊泡也不处于稳定状态。另外，我们揭示了响应速度在很大程度上取决于超声处理温度（T _u），即，T _u越高，速度越快。总体而言，以上重要发现为我们提供了有关如何设计超声响应纳米颗粒的新见识，并可能为合成翻译无创响应药物载体开辟新途径。