Opening the Fourth Biological Window—Novel Lanthanide-Doped Near-Infrared Emitting Nanoparticles

Trivalent lanthanide (Ln³⁺)-based nanoparticles (NPs) are outstanding candidates for a wide range of sensing, imaging, diagnostic and therapeutic applications. Characterized by an incomplete 4f shell shieled by the outer 5s² and 5p⁶shells, the influence of the host lattice and surrounding environment on the optical properties of lanthanide ions is minimized. This results in long excited-state lifetimes and narrow absorption and emission bands that favour the use of excitation wavelengths in the near-infrared (NIR) region and leads to the emission of light in the ultraviolet (UV), visible, and NIR regions. By tailoring the choice of Ln³⁺ dopants, NIR-to-NIR wavelength conversion becomes possible, allowing for both the excitation and emission wavelengths to be compatible with the so-called biological transparency windows (NIR-I to NIR-III: 700 to 1870 nm). These optical properties make Ln³⁺-based NPs favorable fluorescent probes for biological and biomedical applications. The use of NIR light is of particular interest for overcoming some of the limitations of conventionally used organic molecular fluorescent probes, which require excitation with UV light, including photobleaching, tissue autofluorescence, phototoxicity and limited tissue penetration depths. NIR light matching the biological transparency windows suffers from less scattering and absorption by water and biological tissues, which in turn improves spatial resolution and sensitivity and allows for deeper light penetration depths. Current and past research efforts have primarily focused on the development of fluorescent materials that emit at wavelengths longer than 1000 nm in the NIR-II (1000 to 1350 nm) and NIR-III (1550 to 1870 nm) region, under excitation with NIR-I light (700 to 950 nm). Recently, a fourth biological window (NIR-IV) has been suggested, centered at 2200 nm, but there still presents a significant lack of optical probes, specifically at the nanoscale.<br/>To close this gap, here, we propose novel Ln³⁺-doped NIR-IV emitting NPs to open the fourth biological window for exploration. Using the fast and reliable microwave-assisted thermal decomposition method, NIR-IV emitters praseodymium (Pr³⁺) or holmium (Ho³⁺) and sensitizing ytterbium (Yb³⁺) and/or neodymium (Nd³⁺) were doped into sodium rare earth fluoride (NaREF₄) host lattices to form sub-15 nm NPs. Co-doping with Yb³⁺allows for 980 nm NIR excitation, while the absorption and scattering of the excitation light by biological tissues can be further reduced when using 808 nm excitation, which is achieved through co-doping with Nd³⁺. This presentation will shed light on the influence of NP composition, surface chemistry, and aqueous versus non-aqueous media for NP dispersion on the optical properties, i.e., sought after NIR-IV emission. Seeking potential biomedical (and beyond) applications, we further assessed the performance of these NIR-IV emitters as nanothermometers. Optical thermal sensing allows to extract information on the local temperature of a given system at the nanoscale, including thermal irregularities related to various diseases. Overall, the developed NPs are highly promising to open the fourth biological window for imaging and sensing, and thus, potential innovative biomedical applications.