The unique upconversion properties of rare-earth-doped nanoparticles offers exciting opportunities for biomedical applications, in which near-IR remote activation of biological processes is desired, including in vivo bioimaging, optogenetics, and light-based therapies. Tuning of upconversion in purposely designed core–shell nanoparticles gives access to biological windows in biological tissue. In recent years there have been several reports on NIR-excitable upconverting nanoparticles capable of working in biological mixtures and cellular settings. Unfortunately, most of these nanosystems are based on ytterbium’s upconversion at 980 nm, concurrent with water’s absorption within the first biological window. Thus, methods to produce robust upconverting nanoplatforms that can be efficiently excited with other than 980 nm NIR sources, such as 808 nm and 1064 nm, are required for biomedical applications. Herein, we report a synthetic method to produce aqueous stable upconverting nanoparticles that can be activated with 808 nm excitation sources, thus avoiding unwanted heating processes due to water absorbance at 980 nm. Importantly, these nanoparticles, once transferred to an aqueous environment using an amphiphilic polymer, remain colloidally stable for long periods of time in relevant biological media, while keeping their photoluminescence properties. The selected polymer was covalently modified by click chemistry with two FDA-approved photosensitizers (Rose Bengal and Chlorin e6), which can be efficiently and simultaneously excited by the light emission of our upconverting nanoparticles. Thus, our polymer-functionalization strategy allows producing an 808 nm-activable photodynamic nanoplatform. These upconverting nanocomposites are preferentially stored in acidic lysosomal compartments, which does not negatively affect their performance as photodynamic agents. Upon 808 nm excitation, the production of reactive oxidative species (ROS) and their effect in mitochondrial integrity were demonstrated. In summary, we have demonstrated the feasibility of using photosensitizer-polymer-modified upconverting nanoplatforms that can be activated by 808 nm light excitation sources for application in photodynamic therapy. Our nanoplatforms remain photoactive after internalization by living cells, allowing for 808 nm-activated ROS generation. The versatility of our polymer-stabilization strategy promises a straightforward access to other derivatizations (for instance, by integrating other photosensitizers or homing ligands), which could synergistically operate as multifunctional photodynamic platforms nanoreactors for in vivo applications.

中文翻译：

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具有增强稳定性的808 nm活化核@多壳上转换纳米粒子，可进行有效的光动力治疗。

稀土掺杂纳米粒子的独特上转换特性为生物医学应用提供了令人兴奋的机会，其中需要近红外远程激活生物过程，包括体内生物成像，光遗传学和光疗法。特意设计的核-壳纳米粒子的上转换调谐使生物组织中的生物窗口得以进入。近年来，已有几篇有关可在生物混合物和细胞环境中工作的可近红外激发的上转换纳米颗粒的报道。不幸的是，这些纳米系统中的大多数是基于在980 nm处的上转换，以及水在第一个生物窗口内的吸收。因此，产生坚固的上转换纳米平台的方法可以用除980 nm NIR光源以外的其他光源有效激发，例如生物医学应用需要808 nm和1064 nm。在本文中，我们报告了一种合成方法，可生产可被808 nm激发源激活的稳定的水性上转换纳米颗粒，从而避免了由于在980 nm处的吸水率而引起的不必要的加热过程。重要的是，这些纳米粒子一旦使用两亲性聚合物转移到水性环境中，便会在相关的生物介质中长时间保持胶体稳定，同时保持其光致发光特性。所选的聚合物通过点击化学与两种FDA批准的光敏剂（Rose Bengal和Chlorin e6）进行了共价键改性，这些光敏剂可以通过我们上转换纳米粒子的发光而有效地同时被激发。从而，我们的聚合物功能化策略允许生产808 nm可激活的光动力学纳米平台。这些上转换的纳米复合材料优先存储在酸性溶酶体区室，这不会对其光动力剂的性能产生负面影响。在808 nm激发下，证明了活性氧化物质（ROS）的产生及其对线粒体完整性的影响。总之，我们已经证明了使用可被808 nm光激发源激活的光敏剂-聚合物修饰的上转换纳米平台用于光动力疗法的可行性。我们的纳米平台在被活细胞内化后仍保持光活性，从而可产生808 nm活化的ROS。