<br>超小纳米粒子的原因和方法,Accounts of Chemical Research

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超小纳米粒子的原因和方法
Accounts of Chemical Research ( IF 16.4 ) Pub Date : 2023-11-15 , DOI: 10.1021/acs.accounts.3c00459
Matthias Epple ₁ , Vincent M Rotello ₂ , Kenneth Dawson ₃

Affiliation

在本报告中，我们描述了我们对超小纳米颗粒的研究，包括它们的独特特性，并概述了它们提供的一些新机会。我们将总结我们对该领域当前状况的看法，并强调我们认为仍有待解决的关键问题。首先，有几种纳米结构尺寸范围，具有性质不同的功能生物属性。广义而言，较大的颗粒（例如，大于 300 nm）往往会更有效地被免疫系统的第一道防线（例如巨噬细胞）清除。在“中等大小”范围（20-300 nm）中，纳米颗粒表面和形状可以通过能量依赖的细胞重组来识别，然后以空间和时间相干的方式进行局部组织。该能量由特定的细胞识别过程控制并提供。颗粒表面设计、内源性非特异性生物分子冠和细胞识别的结构特征之间的关系很复杂，只有有目的地且非常精确设计的纳米颗粒结构才能导航到特定目标。在尺寸足够小的情况下（<10 nm，包括配体壳，与最多几 nm 的核心直径相关），我们进入“准分子状态”，其中内源生物分子环境与超小颗粒表面交换得如此之快，以至于更大的大规模的细胞和免疫识别事件通常被大大简化。例如，超小颗粒可以通过被动扩散穿透组织结构内的细胞和生物屏障，与小分子药物的方式大致相同。一个有趣的问题出现了：在细胞识别和超小准分子尺寸体系的界面上会发生什么？简而言之，超小缀合物可以逃避由更大规模的细胞纳米级识别驱动的防御机制，使它们能够灵活地利用分子相互作用基序与特定靶标相互作用。利用这些现象的建筑控制方面的许多进展已经发生或正在进行。例如，现在可以充分控制合成，可以制造由数百个原子组成的纳米颗粒或由数十个原子组成的准金属簇，并可通过单晶 X 射线结构分析来表征。虽然在有机溶剂中合成原子级精确的簇提出了挑战，但超小纳米颗粒的水基合成可以扩大规模并产生明确的颗粒群。超小纳米颗粒的表面可以用多种配体进行共价修饰，以控制这些颗粒与生物系统以及药物和荧光团的相互作用。而且，与较大的颗粒相比，可以应用许多先进的分子分析和分离工具来了解它们的结构。例如，核磁共振波谱使我们能够获得颗粒表面和附着的配体的详细图像。这些都是相当大的优势，可以进一步阐述获得新颖功能机制和结果所需的超小型结构的体系结构控制水平和特征。超小纳米粒子体系具有独特的地位，并提供了一个潜在的非常有趣的发展方向。

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The Why and How of Ultrasmall Nanoparticles

In this Account, we describe our research into ultrasmall nanoparticles, including their unique properties, and outline some of the new opportunities they offer. We will summarize our perspective on the current state of the field and highlight what we see as key questions that remain to be solved. First, there are several nanostructure size-scale regimes, with qualitatively distinct functional biological attributes. Broadly generalized, larger particles (e.g., larger than 300 nm) tend to be more efficiently swept away by the first line of the immune system (for example macrophages). In the “middle-sized” regime (20–300 nm), nanoparticle surfaces and shapes can be recognized by energy-dependent cellular reorganizations, then organized locally in a spatial and temporally coherent way. That energy is gated and made available by specific cellular recognition processes. The relationship between particle surface design, endogenously derived nonspecific biomolecular corona, and architectural features recognized by the cell is complex and only purposefully and very precisely designed nanoparticle architectures are able to navigate to specific targets. At sufficiently small sizes (<10 nm including the ligand shell, associated with a core diameter of a few nm at most) we enter the “quasi-molecular regime” in which the endogenous biomolecular environment exchanges so rapidly with the ultrasmall particle surface that larger scale cellular and immune recognition events are often greatly simplified. As an example, ultrasmall particles can penetrate cellular and biological barriers within tissue architectures via passive diffusion, in much the same way as small molecule drugs do. An intriguing question arises: what happens at the interface of cellular recognition and ultrasmall quasi-molecular size regimes? Succinctly put, ultrasmall conjugates can evade defense mechanisms driven by larger scale cellular nanoscale recognition, enabling them to flexibly exploit molecular interaction motifs to interact with specific targets. Numerous advances in control of architecture that take advantage of these phenomena have taken place or are underway. For instance, syntheses can now be sufficiently controlled that it is possible to make nanoparticles of a few hundreds of atoms or metalloid clusters of several tens of atoms that can be characterized by single crystal X-ray structure analysis. While the synthesis of atomically precise clusters in organic solvents presents challenges, water-based syntheses of ultrasmall nanoparticles can be upscaled and lead to well-defined particle populations. The surface of ultrasmall nanoparticles can be covalently modified with a wide variety of ligands to control the interactions of these particles with biosystems, as well as drugs and fluorophores. And, in contrast to larger particles, many advanced molecular analytical and separation tools can be applied to understand their structure. For example, NMR spectroscopy allows us to obtain a detailed image of the particle surface and the attached ligands. These are considerable advantages that allow further elaboration of the level of architectural control and characterization of the ultrasmall structures required to access novel functional regimes and outcomes. The ultrasmall nanoparticle regime has a unique status and provides a potentially very interesting direction for development.

更新日期：2023-11-15

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