Although upconversion nanoparticles (UCNPs) have drawn increasing attention for their unique photophysical characteristics, they suffer from a bottleneck of low luminescence efficiency due to the poor absorption coefficient of Ln 3+ . Dye sensitization has provided thousands-fold enhancement of upconversion luminescence (UCL) in organic solvents because of the remarkably improved light absorption ability, but the sensitization of UCL in aqueous phase is only less than 20 folds by far, with unknown restrictive factors. Herein, the aggregation-caused quenching (ACQ) of dyes is revealed as the most important reason limiting dye sensitization in aqueous phase, and the problem is circumvented through delicately modulating the physical properties of dyes and their assembly manner with UCNPs. By further alleviating energy back transfer (EBT) from Ln 3+ to dyes, more than 600-fold enhancement of UCL is achieved in aqueous phase. The as-obtained dyes modified UCNPs show good biocompatibility and high signal contrast when applied for deep in vivo imaging.suitable for biological applications including bioimaging, biosensing, drug delivery, phototherapy, and so on. [3] However, due to the parity-forbidden nature of the 4f-4f electronic transitions of lanthanide ions, UCNPs suffer from poor light absorption [4] and accordingly extremely low luminescence efficiency and faint brightness, which impairs their performance in practical applications.In a pioneering work of 2012, Hummelen et al. put forward a dye-sensitization strategy to improve UCL intensity in organic solvent. Different from direct absorption of the excitation light by lanthanide ions, heptamethine cyanine with a much larger absorption cross section was employed as an antenna to absorb the energy of photons and transferred its excited-state energy to Ln 3+ ions through a resonance energy transfer pathway. [5] Owing to the dramatically enhanced light absorption ability, thousands-fold enhancement of UCL in organic phase has been achieved through the dye-sensitization process. [6] Considering the requirements of biological applications, efforts have also been devoted to the sensitization of UCL in aqueous phase. [7] Unfortunately, the sensitization efficiency in aqueous phase is badly restricted. In the past few years, although various structures and composition of UCNPs have been tried, this embarrassing situation changes very slowly. [8] Up to now, the highest enhancement factor of dye sensitization of UCL reported in aqueous phase was only 17-fold. [7a] This means that in a biological aqueous environment, the dye-sensitization strategy is not yet able to provide a solution to the bottleneck of UCL brightness. More importantly, the key factors restricting dye sensitization in aqueous phase are unclear so far.In this work, by delicately modulating the properties of dyes as well as their assembly manner with UCNPs, we discovered the factors that decide the sensitization efficiency. In previous dye-sensitized UCL systems in aqueous phase, dyes were assembled wi...

A reliable tool for real-time tracking the neuroinflammatory progress is highly desired for interpretation and treatment of neurological disorders. Herein, a blood–brain barrier (BBB) permeable and HOCl-activatable upconversion (UC) nanoprobe with NIR emission was designed for visual study on neuroinflammation (NI) in vivo. This UC probe consists of three parts: upconversion nanoparticles (UCNPs) as signal reporter, the Cy-HOCl dye acting as energy acceptor of UCNPs as well as the recognition unit of HOCl, and amphiphilic polymers endowing the probe with biocompatibility and BBB permeability. Upon intravenous injection into mice, the probe crossed the BBB via low-density lipoprotein receptor related protein (LRP) mediated transcytosis and was then lightened up by overproduced HOCl in an NI process. This probe was able to differentiate inflammation and the normal state of the brain in LPS-induced NI and monitor the progress of NI occurring in mice with cerebral stroke, providing a practical tool for noninvasive and visual assessment of NI.

When fabricating ratiometric optical probes using lanthanide-doped upconversion nanoparticles (UCNPs), which are promising luminescent materials that have widely been utilized in biosensing and bioimaging as energy donors, it is still a challenge to obtain the emission signal of energy acceptors with reasons unclear so far. Herein, we reveal that the energy-transfer efficiency and brightness of UCNPs as well as the aggregation-caused quenching (ACQ) of energy accepting dyes are the main factors restricting the emission of energy acceptors, and we have circumvented this problem by modulating the structure of UCNPs and the assembly manner of the energy donor−acceptor pair. On this basis, a proof-ofconcept ratiometric upconversion nanoprobe was constructed for hydrogen sulfide (H 2 S) detection with an elaborate dye Fl-1 as an energy acceptor. As the H 2 S concentration increased, the emission intensity of Fl-1 at 525 nm increased gradually, accompanied by a decrease of upconversion luminescence at 480 nm, thus providing a ratiometric signal of F 480 /F 525 dependent on the H 2 S concentration. This probe was able to track H 2 S in living cells and zebrafish and visualize the H 2 S level of mice in physiological processes.

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Nitroxyl (HNO), produced by nitric oxide (NO) with one-electron reduction and protonation, has recently received substantial interest due to its important roles in various biological functions and pharmacological activities. Research indicates that HNO also has many potential pharmacological applications for different diseases. Therefore, the development of a reliable method for HNO assay in biosystems is highly desired. Ratiometric fluorescent probes show significant advantages over traditional "turn-on" ones, because simultaneous measurement of two emission signals can provide a built-in correction and thus minimize the inaccurate fluorescence signal readouts. As far as we know, there is no ratiometric fluorescent probe for HNO detection based on upconversion nanoparticles (UCNPs). Herein, a ratiometric nanoprobe for HNO assay was constructed based on the luminescence resonance energy transfer (LRET) principle by using UCNPs with a core-shell structure (NaYbF 4 :30%Gd@NaYF 4 :2%Yb:1%Tm) as the energy donor and an organic dye Fl-TP as the potential energy acceptor. The oleate-coated UCNPs (OA-UCNPs) and Fl-TP were assembled through hydrophobic interaction to construct the upconversion nanoprobe (termed as Fl-TP-UCNPs). Because of the ring-closed form, Fl-TP displayed weak absorption and was non-fluorescent, which blocked the LRET process. After reaction with HNO, the triphenylphosphine moiety left and released Fl-HNO with the fluorescent ring-open form. Fl-HNO showed strong absorption in the range of 400～500 nm, which completely overlapped with the blue luminescence of UCNPs and triggered the LRET process between UCNPs and Fl-HNO. Thus, the luminescence from UCNPs around 480 nm decreased and the emission from Fl-HNO around 525 nm increased with a [HNO]-dependent manner. The ratiometric luminescence intensity F 525 nm /F 480 nm showed a good linear relationship (R 2 ＝0.9914) to the logarithm of AS (Angeli's salt, a generally used HNO donor) concentration in the range of 3～ 100 μmol•L -1 and the limit of detection was 23.4 nmol•L -1 . The excellent sensitivity, stability, selectivity and low cytotoxicity endow Fl-TP-UCNPs with the superior capability for HNO assay in vitro and in vivo. We found that Fl-TP-UCNPs probe is appropriate for monitoring HNO in living cells as well as imaging HNO in liver tissues. This probe may be a powerful tool for HNO assay in various physiological processes.