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The stunning optical properties of upconverting nanoparticles (UCNPs) have inspired promising and unique biomedical technologies. However, as a necessary step for their use in bio-applications, their transfer to aqueous media is accompanied by highly detrimental effects. Namely, intense luminescence quenching and partial dissolution by water, as well as complete degradation by other molecules such as phosphates. Whereas the translation of UCNPs to the medical market would open new and interesting avenues for ultrasensitive diagnostics and other medical technologies, their concentration- and time-dependent degradation currently challenges the realistic bio-application of these nanomaterials. In this work, we developed a strategy to protect UCNPs by creating an isolating hydrophobic polymer shell (HPS) through miniemulsion polymerization. Stability studies revealed that these HPS served as a very effective barrier, impeding polar molecules to affect UCNP’s optical properties. Even more, it allowed UCNPs to withstand even extremely aggressive conditions such as very high dilutions, high phosphate concentrations, and high temperatures. In-depth optical, morphological, and atomic-level chemical characterization proved the potential of HPS to overcome the current limitations of UCNPs. This strategy, which can be applicable to other nanomaterials with similar limitations, pave the way towards more stable and reliable UCNPs with expanded applications in life sciences.&nbsp

Luminescent nano-thermometry is a fast-developing technique with great potential for in vivo sensing, diagnosis, and therapy. Unfortunately, it presents serious limitations. The luminescence generated by nanothermometers, from which thermal readout is obtained, is strongly distorted by the attenuation induced by tissues. Such distortions lead to low signal levels and entangle absolute and reliable thermal monitoring of internal organs. Overcoming both limitations requires the use of high-brightness luminescent nanothermometers and adopting more complex approaches for temperature estimation. In this work, it is demonstrated how superbright Ag2S nanothermometers can provide in vivo, reliable, and absolute thermal reading of the liver during laser-induced hyperthermia. For that, a new procedure is designed in which thermal readout is obtained from the combination of in vivo transient thermometry measurements and in silico simulations. The synergy between in vivo and in silico measurements has made it possible to assess relevant numbers such as the efficiency of hyperthermia processes, the total heat energy deposited in the liver, and the relative contribution of Ag2S nanoparticles to liver heating. This work provides a new way for absolute thermal sensing of internal organs with potential application not only to hyperthermia processes but also to advanced diagnosis and therapy., This work was supported by the Spanish Ministry of Economy and Competitiveness under projects MAT2016-75362-C3-1-R, MAT2017-83111R, and MAT2017-85617-R, by the Instituto de Salud Carlos III (PI16/00812), by the Comunidad Autonoma de Madrid (B2017/BMD-3867 RENIM-CM), and cofinanced by the European Structural and investment fund. Additional funding was provided by the European Union's Horizon 2020 FET Open programme (Grant Agreement No. 801305, NanoTBTech), the Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal project IMP18_38 (2018/0265), and also by COST action CA17140. Y.S. acknowledges a scholarship from the China Scholarship Council (No. 201806870023). I.Z.G. thanks UCM-Santander for a predoctoral contract (CT63/19-CT64/19). D.O. and I.R. acknowledge financial support from the Community of Madrid under Contract No. PEJD-2017-PRE/IND-3663, and from the Spanish Ministry of Science and Innovation through the Ramon y Cajal grant RYC2018-025253-I, Research Networks grant RED2018-102626-T and the PID2019-106211RB-I00 grant as well as the Ministry of Economy and Competitiveness through the grants MAT2017-85617-R, MAT2017-88148R and the "Severo Ochoa" Program for Centers of Excellence in R&D (SEV-2016-0686). D.O. and I.R. also acknowledge support from the "NoCanTher" project, which has received funding from the European Union's Horizon 2020 research and innovation programme under Grant Agreement No. 685795. E.X. is grateful for a Juan de la Cierva Formacion scholarship (FJC2018-036734-I).

We present a sensor that exploits the phenomenon of upconversion luminescence to detect the presence of specific sequences of small oligonucleotides such as miRNAs among others. The sensor is based on NaYF4:Yb,Er@SiO2 nanoparticles functionalized with ssDNA that contain azide groups on the 3' ends. In the presence of a target sequence, interstrand ligation is possible via the click-reaction between one azide of the upconversion probe and a DBCO-ssDNA-biotin probe present in the solution. As a result of this specific and selective process, biotin is covalently attached to the surface of the upconversion nanoparticles. The presence of biotin on the surface of the nanoparticles allows their selective capture on a streptavidin-coated support, giving a luminescent signal proportional to the amount of target strands present in the test samples. With the aim of studying the analytical properties of the sensor, total RNA samples were extracted from healthy mosquitoes and were spiked-in with a specific target sequence at different concentrations. The result of these experiments revealed that the sensor was able to detect 10-17 moles per well (100 fM) of the target sequence in mixtures containing 100 ng of total RNA per well. A similar limit of detection was found for spiked human serum samples, demonstrating the suitability of the sensor for detecting specific sequences of small oligonucleotides under real conditions. In contrast, in the presence of noncomplementary sequences or sequences having mismatches, the luminescent signal was negligible or conspicuously reduced. The authors are grateful for the financial support from the Bill & Melinda Gates Foundation, with Grant OPP1128411, Asociación Española Contra el Cáncer, Santander-Universidad Complutense project PR26/16-12B-3, and from the Spanish MINECO for the projects MAT2014-55065-R, SAF2014-56763-R, and FIS2013-41709-P. Sí