Recent progress in upconversion nanomaterials for emerging optical biological applications

Highlights

• A variety of applications of upconversion nanoparticles (UCNPs) in biology are reviewed, including visualization, detection, imaging, therapeutics, and diagnostics, with applications to the near-infrared (NIR) being the main feature.

• The emission and structure characteristics of UCNPs are among the reasons for their potential in visualization and optical devices.

• The multifunctional nanoplatforms of UCNPs used at the cellular level are an innovative, precise, and quantifiable three-dimensional model.

• UCNPs play an important role as a functional component of photoconversion in a variety of therapeutic procedures that use light as a switch.

Abstract

The recent advances of upconversion nanoparticles (UCNPs) have made them the ideal “partner” for a variety of biological applications. In this review, we describe the emerging biological optical applications of UCNPs, focus on their potential therapeutic advantages. Firstly, we briefly review the development and mechanisms of upconversion luminescence, including organic and inorganic UCNPs. Next, in the section on UCNPs for imaging and detection, we list the development of UCNPs in visualization, temperature sensing, and detection. In the section on therapy, recent results are described concerning optogenetics and neurotherapy. Tumor therapy is another major part of this section, including the synergistic application of phototherapy such as photoimmunotherapy. In a special section, we briefly cover the integration of UCNPs in therapeutics. Finally, we present our understanding of the limitations and prospects of applications of UCNPs in biological fields, hoping to provide a more comprehensive understanding of UCNPs and attract more attention.

Introduction

Since the beginning of the 21st century, research on upconversion nanoparticles (UCNPs) has rapidly developed in theoretical and applied fields [1], [2]. The photonic upconversion phenomenon was first observed experimentally in the 1960s by Francois Azuel, who showed that low-energy infrared light could be emitted at visible wavelengths in Yb-Er and Er-Tm systems after an intersystem energy transfer, suggesting the existence of excited-state charge transfer between two excited ions in transition metal lattices doped with rare earth metals [3], [4]. In 1972, Menyuk et al. achieved a Yb/Er-doped fluoride lattice, which was the first example of the effective doping of lanthanides [5]. The multiple f-energy levels of rare-earth particles provide multiple leap pathways for their upconversion processes in the luminescence process. Rare earth particles absorb photon energy to produce luminescence through Förster resonance energy transfer (FRET) or Dexter energy transfer (DET) processes that transfer energy to the activator [6], [7].

For the need for diagnostic imaging of diseases in research and fluorescent probes in organisms, a variety of probes and reagents have been developed, such as organic dyes [8], organically modified silica [9], [10], fluorescent proteins [11], [12], [13], metal complexes [14], [15], [16], and semiconductor quantum dots [17]. However, conventional agents usually have many limitations: high-energy short-wavelength excitation with low penetration depth, potential DNA toxicity, autofluorescence, and scattering by fur or skin. Rapid advances in nanotechnology and biotechnology have led to strong interest in the use of UCNPs with excellent optical properties in the biological and medical fields. It is worth mentioning that the application of upconversion nanomaterials in biology has a long history [18], [19]. In the 1999s, Zijlmans et al. were the first to use the upconversion properties of lanthanide-doped phosphors to study biometric events. They used phosphors with antibiotic proteins or antibodies to specifically bind to CD4 membrane antigens of human lymphocytes for visualization [20]. Zhao et al. created a near-infrared (NIR) light-triggered drug release system by loading 7-amino-coumarin derivative-caged anticancer drug chlorambucil in upconversion nanophosphors [21]. And Chatterjee et al. demonstrated a new upconversion fluorophore used for cellular and tissue imaging first [22]. On this basis, upconversion nanomaterials are used in many fields such as upconversion fluorescence imaging, magnetic resonance imaging (MRI), phototherapy [23], optogenetics [24], super-resolution imaging [25], and infrared visual imaging [26]. Upconversion luminescence allows it to be excited in the near-infrared biological window (650–1700 nm) for upconversion luminescence (UCL), which leads to less bioabsorption and deeper penetration properties [27], [28]. In addition, the tunable doping mode and structural morphology of UCNPs bring it targeted narrow-band luminescence and stable physicochemical properties in a wide range of environments. These foundations make UCNPs promising for novel biological applications. Here is a representative event. Indocyanine green (ICG) is a widely used clinical contrast agent, photosensitizer, and photothermal agent. ICG strongly absorbs near-infrared light near 800 nm and generates fluorescence, as well as reactive oxygen species (ROS) and heat. Therefore, ICG is widely used in clinical imaging, photodynamic and photothermal therapy [29], [30], [31], [32]. For well-known reasons, ICG is rapidly cleared after entering the body, easily burst by the body's water-oxygen environment, and not specific [33]. The use of a series of UCNPs-ICG has demonstrated that stable upconversion nanoparticles are a better “partner” for a variety of fluorescent probes [34], [35], [36], [37], [38], [39], [40]. The upconversion immune-nanohybrids (UINBs) developed by Jin's group have the ability to detect prostate cancer cells with a high degree of specificity due to specific non-background and optical stabilization of UCNP properties, as well as colloidal stability and streptavidin (SA)-biotin-driven antibody conjugation [41]. Here, Table 1 lists more comparisons of UCNPs probes and traditional fluorescent probes.

We note that UCNPs have made rapid progress in recent years, which makes it necessary to review the latest advances in time. In this review, we enumerate recent attractive advances in optical-biological aspects of UCNPs, including single-particle imaging, single-cell vesicle imaging, and NIR visualization. In addition, we review recent advances in the therapeutic and diagnostic aspects of UCNPs. Finally, we summarize the prospects and challenges of UCNPs, hoping to bring inspiration to reveal more mechanisms in biological imaging and therapy by presenting the applications of UCNPs from multiple perspectives (Scheme 1).