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Here, we describe the design of a molecular probe (NB-ALA) based on the Nile Blue fluorophore, which can detect alanine aminopeptidase enzyme (a kidney damage biomarker) in urine by simple fluorometric measurements.

[EN] Synthetic cathinones are a class of new psychoactive substances whose consumption has increased a lot and is widespread throughout the world. Thus, there is currently a need for rapid and simple detection of these drugs. In particular, detection of synthetic cathinones in oral fluid in drivers can be of great importance in preventing traffic accidents. Herein, we report two probes, based on BODIPY derivatives combined with Cu(ii), which are able to detect these drugs both in water and in oral fluid, by changes in color and fluorescence. The determined limits of detection for ephedrone (as a model drug) are lower than the usual concentrations in saliva after intake of this type of drug. The sensing mechanism seems to be related to the cathinone induced reduction of Cu(ii) to Cu(i) with concomitants changes in the BODIPY structure., We thank the Spanish Government, MCIN/AEI/10.13039/501100011033 and "ERDF A way of making Europe" (fund RTL2018-100910-B-C42), the Spanish Ministry of Health, Consumer Affairs and Social Welfare (Project 2020I040 PNSD 2020) and Generalitat Valenciana (PROMETEO 2018/024) for financial support. SCSIE (Universitat de Valencia) is gratefully acknowledged for all the equipment employed. NMR was registered at the U26 facility of ICTS "NAMBIOSIS" at the Universitat of Valencia.

Cellular senescence is a stable cell cycle arrest in response to stress or other damage stimuli to maintain tissue homeostasis. However, the accumulation of senescent cells can lead to the progression of various senescence-related disorders. In this paper, we describe the development of a β-galactosidase-activatable near-infrared (NIR) senoprobe

Acute lung injury (ALI) is a critical inflammatory syndrome, characterized by increased diffuse inflammation and severe lung damage, which represents a clinical concern due to the high morbidity and mortality in critical patients. In last years, there has been a need to develop more effective treatments for ALI, and targeted drug delivery to inflamed lungs has become an attractive research field. Here, we present a nanodevice based on mesoporous silica nanoparticles loaded with dexamethasone (a glucocorticoid extensively used for ALI treatment) and capped with a peptide that targets the TNFR1 receptor expressed in pro-inflammatory macrophages (TNFR-Dex-MSNs) and avoids cargo leakage. TNFR-Dex-MSNs nanoparticles are preferentially internalized by pro-inflammatory macrophages, which overexpressed the TNFR1 receptor, with the subsequent cargo release upon the enzymatic hydrolysis of the capping peptide in lysosomes. Moreover, TNFR-Dex-MSNs are able to reduce the levels of TNF-α and IL-1β cytokines in activated pro-inflammatory M1 macrophages. The anti-inflammatory effect of TNFR-Dex-MSNs is also tested in an in vivo ALI mice model. The administered nanodevice (intravenously by tail vein injection) accumulated in the injured lungs and the controlled dexamethasone release reduces markedly the inflammatory response (TNF-α IL-6 and IL-1β levels). The attenuation in lung damage, after treatment with TNFR-Dex-MSNs, is also confirmed by histopathological studies. Besides, the targeted-lung dexamethasone delivery results in a decrease of dexamethasone derived side-effects, suggesting that targeted nanoparticles can be used for therapy in ALI and could help to overcome the clinical limitations of current treatments.

The construction of a novel enzyme-controlled nanomachine with multiple release mechanisms for on-command delivery is described. This nanodevice was assembled by modifying mesoporous silica nanoparticles with 2-(benzo[d]thiazol-2-yl)phenyl 4-aminobenzoate moieties, and further capped with beta-cyclodextrin-modified glucose oxidase neoglycoenzyme. The device released the encapsulated payload in the presence of H2O2 and acidic media. The use of glucose as an input chemical signal also triggered cargo release through the enzymatic production of gluconic acid and hydrogen peroxide, and the subsequent disruption of the gating mechanism at the mesoporous surface. The nanodevice was successfully employed for the enzyme-controlled release of doxorubicin in HeLa cancer cells.

[EN] beta-Galactosidase (beta-Gal) is a widely used enzyme as a reporter gene in the field of molecular biology which hydrolyzes the beta-galactosides into monosaccharides. beta-Gal is an essential enzyme in humans and its deficiency or its overexpression results in several rare diseases. Cellular senescence is probably one of the most relevant physiological disorders that involve beta-Gal enzyme. In this review, we assess the progress made to date in the design of molecular-based probes for the detection of beta-Gal both in vitro and in vivo. Most of the reported molecular probes for the detection of beta-Gal consist of a galactopyranoside residue attached to a signalling unit through glycosidic bonds. The beta-Gal-induced hydrolysis of the glycosidic bonds released the signalling unit with remarkable changes in color and/or emission. Additional examples based on other approaches are also described. The wide applicability of these probes for the rapid and in situ detection of de-regulation beta-Gal-related diseases has boosted the research in this fertile field, R.M laboratory members received the financial support from the Spanish Government (project RTI2018-100910-B-C41) and the Generalitat Valenciana (project PROMETEO 2018/024). B.L-T. received support from the Spanish Ministry of Economy for their PhD grants (FPU15/02707). J. F.-B received fellowship (CD19/00038)

[EN] Celiac disease is a complex and autoimmune disorder caused by the ingestion of gluten affecting almost 1% of global population. Nowadays an effective treatment does not exist, and the only way to manage the disease is the removal of gluten from the diet. Owing the key role played by gluten, clear and regulated labelling of foodstuff and smart methods for gluten detection are needed to fight frauds on food industry and to avoid the involuntary ingestion of this protein by celiac patients. On that scope, the development of a novel detection system of gluten is here presented. The sensor consists of nanoporous anodic alumina films loaded with a fluorescent dye and capped with an aptamer that recognizes gliadin (gluten's soluble proteins). In the presence of gliadin, aptamer sequences displace from the surface of anodic alumina resulting in pore opening and dye delivery. The dispositive shows a limit of detection (LOD) of 100 mu g kg(-1) of gliadin, good selectivity and a detection time of approximately 60 min. Moreover, the sensor is validated in real food samples. This novel probe allows fast gluten detection through a simple signalling process with potential use for food control. (C) 2020 Elsevier B.V. All rights reserved., The authors want to thank the Spanish Government RTI2018-100910-B-C41 (MCUI/AEI/FEDER, UE) and the Generalitat Valenciana (project PROMETEO/2018/024) for support. L.P. thanks to Ministerio de Economia, Industria y Competitividad for his FPI grant. S.S.-F. thanks CIBER and ISCIII for her Sara Borrell contract. The authors also thank the Electron Microscopy Service at the UPV for support.

This work describes the assembly of a novel enzyme-controlled nanomachine operated through an AND Boolean logic gate for on-command delivery. The nanodevice was constructed on Au-mesoporous silica Janus nanoparticles capped with a thiol-sensitive gate-like molecular ensemble on the mesoporous face and functionalized with glutathione reductase on the gold face. This autonomous nanomachine employed NADPH and glutathione disulfide as input chemical signals, leading to the enzymatic production of reduced glutathione that causes the disruption of the gating mechanism on the mesoporous face and the consequent payload release as an output signal. The nanodevice was successfully used for the autonomous release of doxorubicin in HeLa cancer cells and RAW 264.7 macrophage cells.

[EN] The characteristics and electromechanical properties of conductive polymers together to their biocompatibility have boosted their application as a suitable tool in regenerative medicine and tissue engineering. However, conducting polymers as drug release materials are far from being ideal. A possibility to overcome this drawback is to combine conducting polymers with on-command delivery particles with inherent high-loading capacity. In this scenario, we report here the preparation of conduction polymers containing gated mesoporous silica nanoparticles (MSN) loaded with a cargo that is delivered on command by electro-chemical stimuli increasing the potential use of conducting polymers as controlled delivery systems. MSNs are loaded with Rhodamine B (Rh B), anchored to the conductive polymer poly(3,4-ethylenedioxythiophene) (PEDOT) doped with poly[(4-styrenesulfonic acid)-co-(maleic acid)], functionalized with a bipyridinium derivative and pores are capped with heparin (P3) by electrostatic interactions. P3 releases the entrapped cargo after the application of ¿640 mV voltage versus the saturated calomel electrode (SCE). Pore opening in the nanoparticles and dye delivery is ascribed to both (i) the reduction of the grafted bipyridinium derivative and (ii) the polarization of the conducting polymer electrode to negative potentials that induce detachment of positively charged heparin from the surface of the nanoparticles. Biocompatibility and cargo release studies were carried out in HeLa cells cultures., Alba Garcia-Fernandez, Beatriz Lozano-Torres contributed equally to this work. A. Garcia-Fernandez and B. Lozano-Torres are grateful to the "Ministerio de Economia y Competitividad" of the Spanish Government for her PhD fellowships. J. F. Blandez thanks the "Universitat Politecnica de Valencia" for his postdoctoral fellowship (PAID-10-17). The authors thank to the Spanish Government (Projects RTI2018-100910-B-C41 and RTI2018-101599-B-C22 (MCUI/AEI/FEDER, EU)) and the Generalitat Valencia (Project PROMETEO2018-024) for support.

Two new oxazole derivatives, able to detect γ-hydroxybutyric acid (GHB) in soft drinks and alcoholic beverages, by color and fluorescence changes, are reported.

The incorporation by ionic assembly of the hexanuclear molybdenum cluster (Bu

The engineering of chemical communication at the micro/nanoscale is a key emergent topic in micro/nanotechnology, synthetic biology, and related areas. However, the field is still in its infancy; previous advances, although scarce, have mainly focused on communication between abiotic micro/nanosystems or between microvesicles and living cells. Here, we have implemented a nanoprogrammed cross-kingdom communication involving two different microorganisms and tailor-made nanodevices acting as "nanotranslators". Information flows from the sender cells (bacteria) to the nanodevice and from the nanodevice to receiver cells (yeasts) in a hierarchical way, allowing communication between two microorganisms that otherwise would not interact.

[EN] Cage compounds offer unique binding pockets similar to enzyme-binding sites, which can be customized in terms of size, shape, and functional groups to point toward the cavity and many other parameters. Different synthetic strategies have been developed to create a toolkit of methods that allow preparing tailor-made organic cages for a number of distinct applications, such as gas separation, molecular recognition, molecular encapsulation, hosts for catalysis, etc. These examples show the versatility and high selectivity that can be achieved using cages, which is impossible by employing other molecular systems. This review explores the progress made in the field of fully organic molecular cages and containers by focusing on the properties of the cavity and their application to encapsulate guests., V.M.-C. acknowledges the financial support from project CIDEGENT/2020/031 funded by the Generalitat Valenciana and project PID2020-113256RA-I00 funded by MCIN/AEI/10.13039/501100011033. R.M.-M. and F.S. acknowledge the financial support from project PROMETEO 2018/024 from the Generalitat Valenciana and project RTI2018-100910-B-C41 funded by MCIN/AEI/10.13039/501100011033/and FEDER A way to make Europe. Funding for open access charge: CRUE-Universitat Politecnica de Valencia.

[EN] We report herein the design of a strip-based rapid test utilizing bio-inspired hybrid nanomaterials for the in situ and at site detection of the drug scopolamine (SCP) using a smartphone for readout, allowing SCP identification in diluted saliva down to 40 nM in less than 15 min. For this purpose, we prepared a nanosensor based on mesoporous silica nanoparticles loaded with a fluorescent reporter (rhodamine B) and functionalized with bethanechol, a potent agonist of recombinant human muscarinic acetylcholine receptor M-2 (M-2-AChR). M-2-AChR interaction with the anchored bethanechol derivative leads to capping of the pores. The sensing mechanism relies on binding of SCP to M-2-AChR resulting in pore opening and delivery of the entrapped rhodamine B reporter. Moreover, the material was incorporated into strips for lateral-flow assays coupled to smartphone readout, giving fast response time, good selectivity, and exceptional sensitivity. In an attempt to a mobile analytical test system for law enforcement services, we have also developed a dualplex lateral flow assay for SCP and 3,4-methylenedioxypyrovalerone (MDPV) also known as the so-called "cannibal drug"., This research was funded by the Ministerio de Ciencia, Innovacion y Universidades (Spanish Government), the Agencia Estatal de Investigacion (AEI), the European Union (projects RTI2018-100910-B-C41 and RTI2018-101599-B-C22-AR (MCIU/AEI/FEDER, EU), the Conselleria de Innovacion, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana (Project PROMETEO 2018/024) and the German Research Foundation (DFG; CL 761/1-19). E. G. is grateful to the Spanish MEC for her FPU grant (FPU16/02464).

[EN] A new method for senescent cell detection is described, which is based on lipofuscin labeling with a fluorescent reporter through a biorthogonal strain-promoted azide-alkyne cycloaddition. The sensing protocol involves a first step where the interaction of lipofuscin with a Sudan Black B derivative containing an azide moiety (SBB-N3 ) is carried out. In the final step, the azide moiety reacts with a fluorophore containing a cyclooctene ring (BODIPY). The efficacy of this two-step protocol is assessed in senescent melanoma SK-MEL-103 cells, senescent triple-negative breast cancer MDA-MB-231 cells and senescent WI-38 fibroblasts. In all cases, a clear fluorescence pattern was observed in senescent cells, compared to proliferative cells, only when the SBB-N3 -BODIPY probe was formed. Our results provide an alternative tool for the detection of senescent cells, based on an in situ bio-orthogonal reaction for lipofuscin labeling, RM laboratory members are grateful for financial support from the FEDER foundation of European Union (IDIFEDER/2021/044), the Spanish Government (projects RTI2018-100910-B-C41 and RTI2018-101599-B-C22) and the Generalitat Valenciana (project PROMETEO 2018/024). BL-T and AG-F acknowledge their current Margarita Salas postdoctoral fellowship from UPV-MIU and 'Next Generation EU' program. JF-B is grateful for his Sara Borrell postdoctoral fellowship (CD19/00038).

The main cause of subretinal neovascularisation in wet age-related macular degeneration (AMD) is an abnormal expression in the retinal pigment epithelium (RPE) of the vascular endothelial growth factor (VEGF). Current approaches for the treatment of AMD present considerable issues that could be overcome by encapsulating anti-VEGF drugs in suitable nanocarriers, thus providing better penetration, higher retention times, and sustained release. In this work, the ability of large pore mesoporous silica nanoparticles (LP-MSNs) to transport and protect nucleic acid molecules is exploited to develop an innovative LP-MSN-based nanosystem for the topical administration of anti-VEGF siRNA molecules to RPE cells. siRNA is loaded into LP-MSN mesopores, while the external surface of the nanodevices is functionalised with polyethylenimine (PEI) chains that allow the controlled release of siRNA and promote endosomal escape to facilitate cytosolic delivery of the cargo. The successful results obtained for VEGF silencing in ARPE-19 RPE cells demonstrate that the designed nanodevice is suitable as an siRNA transporter.

[EN] The construction of communication models at the micro¿/nanoscale involving abiotic nanodevices and living organisms has the potential to open a wide range of applications in biomedical and communication technologies. However, this area remains almost unexplored. Herein, we report, as a proof of concept, a stimuli¿responsive interactive paradigm of communication between yeasts (as a model microorganism) and enzyme¿controlled Janus Au¿mesoporous silica nanoparticles. In the presence of the stimulus, the information flows from the microorganism to the nanodevice, and then returns from the nanodevice to the microorganism as a feedback., B.dL. is grateful to the Spanish Government for her FPU PhD fellowship. The authors wish to thank the Spanish Government (projects RTI2018-100910-B-C41 (MCUI/AEI/FEDER, UE) and CTQ2017-87954-P), the Generalitat Valenciana (project PROMETEO2018/024), the Comunidad de Madrid (Project IND2017/BMD-7642) and CIBER-BBN (NANOCOM project) for support.

[EN] Here we describe the construction of an integrated and pH-sensitive nanomachine with layer-by-layer supramolecular design and enzymatic control for on-command delivery. The nanodevice comprises a first layer of ß-cyclodextrin-coated gold nanoparticles as capping element of benzimidazole functionalized mesoporous silica nanoparticles, and a second control layer based on an adatamantane-modified glucose oxidase derivative. The nanomachine was selectively fuelled by glucose and successfully employed for the autonomous release of doxorubicin in HeLa cancer cells., Financial support from the Spanish Ministry of Economy and Competitiveness (projects CTQ2014-58989-P, CTQ2015-71936-REDT, CTQ2017-87954-P, and MAT2015-64139-C4-1-R) and generalitat Valenciana (project PROMETEO/2018/024) is gratefully acknowledged.

Senescence is a state of permanent cell cycle arrest. Cellular senescence can promote tissue remodelling but can negatively affect regenerative capacities of tissues and contribute to inflammation and the progression of cancer and ageing-related diseases. This Review highlights the chemical characteristics of senescence and how we can target senescent cells with small molecules to induce senescence in hyperproliferative tissues. Alternatively, these small molecules can also be administered to inhibit senescence or eliminate senescent cells as the basis of a promising strategy to treat ageing-related diseases. We also describe advances in detecting senescence in in vitro and in vivo models, such that we can evaluate response to treatments intended to induce or eliminate senescent cells. Senescence is a state of permanent cell cycle arrest. This Review highlights the chemical characteristics of senescence and how we can use small molecules to target, detect or eliminate senescent cells, as well as to induce or inhibit senescence.

A new simple and easy-to-prepare imidazole-based probe 1 was synthesized and used to detect Cu(II) and biothiols (Cys, Hcy and GSH) in aqueous environments. Addition of increasing amounts of Cu(II) to water (pH 7.4)-acetonitrile 90:10 v/v solutions of probe 1 induced the apperance of a red-shifted absorption together with a marked colour change from colorless to deep blue. In addition, probe 1 was fluorescent and a marked emission quenching in the presence of Cu(II) was observed. The optical response is selective and other cations tested do not induce significant chromo-fluorogenic modulations. Limits of detection for Cu(II) of 0.7 and 3.2 μM using UV–visible and fluorescence data were determined. On the other hand, addition of Cys, Hcy and GSH to the deep-blue water (pH 7.4)-acetonitrile 90:10 v/v solutions of the 1-Cu(II) complex reulted in a marked bleaching together with the appearance of a highly emissive band centred at 475 nm. Other amino acids tested induced negligible response. The limits of detection for Cys, Hcy and GSH using 1-Cu(II) and emission data are 6.5, 5.0 and 10.2 μM, respectively. These optical changes were ascribed to a biothiol-induced demetallation process of the 1-Cu(II) complex that released the free probe. Besides, probe 1 is non-toxic and can be used for Cu(II) detection in HeLa cells., FCT - Generalitat Valenciana(PROMETEOII/2014/047); Spanish Government (projects MAT2015-64139-C4-1-R and AGL2015-70235-C2-2-R) and the Generalitat Valenciana (project PROMETEOII/2014/047). Thanks are also due to Fundação para a Ciência e a Tecnologia for financial support to the Portuguese NMR network (PTNMR, Bruker Avance III 400-Univ. Minho), FCT and FEDER (European Fund for Regional Development)-COMPETEQREN-EU for financial support to the research centre CQ/UM (Ref. UID/QUI/00686/2013 and UID/QUI/0686/2016), and a PhD grant to R. C. M. Ferreira (SFRH/BD/86408/2012), info:eu-repo/semantics/publishedVersion

[EN] A nanodevice based on mesoporous silica nanoparticles with rhodamine B in the pore framework, functionalized with carboxylates on the outer surface and capped with the cationic polymyxin B peptide, was used to selectively detect endotoxin in aqueous solutions with a limit of detection in the picomolar range., The authors thank the Spanish Government (MAT2015 64139-C4-1-R) and the Generalitat Valenciana (PROMETEO2018/024) for their support. I.O. thanks to Erasmus Mundus Programme, Action 2, Lot 1, Syria, for his predoctoral fellowship. S.S. is grateful to Spanish Ministerio de Economia y Competitividad for his Juan de la Cierva contract (FJCI-2015-27201).

[EN] A simple colorimetric probe for the selective and sensitive detection of neurotransmitter norepinephrine (NE), an important biomarker in the detection of tumors such as pheochromocytoma and paraganglioma, is described. The sensing strategy is based on the use of spherical gold nanoparticles functionalized with benzaldehyde and boronic acid-terminated moieties. A double molecular recognition involving on one hand the aromatic aldehyde and the aminoalcohol group of NE, and on the other hand the boronic acid and the catechol moiety of the neurotransmitter, results in analyte triggered aggregation of the gold nanoparticles, leading to a bathochromic shift of the SPR band in the UV-vis spectrum of the probe and a clear change in the color of the solution from red to blue. Probe P1 shows a remarkable selectivity toward NE versus other catecholamine neurotransmitters (dopamine and epinephrine) and selected biomolecules (S-HIAA, L-Tyr, glucose, uric acid, Lys and glutamic acid). Moreover, a linear response to NE in the 0-1 mu M concentration range was observed and a limit of detection of 0.07 mu M in aqueous media was determined by UV-vis spectroscopy. The sensitivity of the probe toward NE in synthetic urine was also evaluated. In this medium, a limit of detection of 0.09 mu M was obtained which falls within the range of clinical interest, Financial support from the Spanish Government (Projects MAT2015-64139-C4-1-R and MAT2015-64139-C4-4-R) and the Generalitat Valencia (Projects PROMETEOII/2014/047 and AICO/2017/093) is gratefully acknowledged. T. Godoy-Reyes is grateful to the Generalitat Valenciana for her Santiago Grisolia fellowship.

Optical sensing offers a low‐cost and effective means to sense carbon monoxide in air and in solution. This contribution reports the synthesis of a new series of vinyl complexes [Ru(CH=CHR)Cl(CO)(TBTD)(PPh3)2] (R = aryl, TBTD = 5‐(3‐thienyl)‐2,1,3‐benzothiadiazole) and shows them to be highly sensitive and selective probes for carbon monoxide in both solution and air. Depending on the vinyl substituent, chromogenic and fluorogenic responses signalled the presence of this invisible, odourless, tasteless and toxic gas. Adsorbing the complexes on silica produced colorimetric probes for the ‘naked eye’ detection of CO in the gas phase with a limit of detection as low as 8 ppm in some cases, while the release of the TBTD fluorophore allowed detection at much lower concentrations through the fluorescence response. Structural data were obtained by single crystal X‐ray diffraction techniques, while the photophysical behaviour was explored computationally using TD‐DFT experiments. The systems were also shown to be selective for CO over all other gases tested, including water vapour and common organic solvents. By introducing a poly(ethylene)glycol chain to the vinyl functionality, water compatibility was achieved and these non‐cytotoxic complexes were employed in the sensing of CO in HeLa cells, offering a simple and rapid system for sensing this gasotransmitter in this challenging medium.

We report herein a L-glutamate (L-Glu)-responsive delivery system. It consists of Janus Au–mesoporous silica (MS) nanoparticles functionalized with L-glutamate oxidase on the Au face and with self-immolative arylboronate derivatives as caps on the MS face. The MS face is additionally loaded with a cargo. The delivery paradigm is based on the recognition of L-Glu by the enzyme and the subsequent formation of H2O2, which induces the cleavage of the self-immolative gate and the uncapping of the pores. Given the importance of L-Glu as a key neurotransmitter, we hope that these findings will help in designing new therapeutic strategies for nervous system diseases.

We report herein the assembly of an integrated nanodevice with bi-enzymatic cascade control for on-command cargo release. This nanocarrier is based on Au-mesoporous silica Janus nanoparticles capped at the mesoporous face with benzimidazole/beta-cyclodextrin-glucose oxidase pH-sensitive gate-like ensembles and functionalized with invertase on the gold face. The rationale for this delivery mechanism is based on the invertase-mediated hydrolysis of sucrose yielding glucose, which is further transformed into gluconic acid by glucose oxidase causing the disruption of the pH-sensitive supramolecular gates at the Janus nanoparticles. This enzyme-powered device was successfully employed in the autonomous and on-demand delivery of doxorubicin in HeLa cancer cells.

Two iodinated (1 and 2) and two brominated (3 and 4) BODIPY-based photosensitizers are prepared and characterized using slightly modified synthetic procedures previously described. 1–4 present intense absorption bands in the 510–540 nm interval and very weak emissions due to the presence of halogen atoms in their structure. Irradiation of aqueous solutions of 1–4 with visible light (wavelength > 475 nm) induce the generation of singlet oxygen with quantum yields of ca. 0.62–0.66 for the photosensitizers containing iodine atoms (1 and 2) and of ca. 0.16–0.21 for the brominated counterparts (3 and 4). In vitro studies carried out with HeLa, SCC-13 and HaCaT cell lines and the four photosensitizers show marked reductions in cell viability with lower IC50 values for the iodinated derivatives (in the 0.82–2.51 range) than those found for the brominated compounds (in the 0.91–8.26 range) suggesting that these compounds could be used in photodynamic therapy protocols. Subcellular localization studies carried out using confocal microscopy show that photosensitizers accumulated in the endoplasmic reticulum.

We report herein a gene-directed enzyme prodrug therapy (GDEPT) system using gated mesoporous silica nanoparticles (MSNs) in an attempt to combine the reduction of side effects characteristic of GDEPT with improved pharmacokinetics promoted by gated MSNs. The system consists of the transfection of cancer cells with a plasmid controlled by the cytomegalovirus promoter, which promotes β-galactosidase (β-gal) expression from the bacterial gene lacZ (CMV-lacZ). Moreover, dendrimer-like mesoporous silica nanoparticles (DMSNs) are loaded with the prodrug doxorubicin modified with a galactose unit through a self-immolative group (DOXO-Gal) and modified with a disulfide-containing polyethyleneglycol gatekeeper. Once in tumor cells, the reducing environment induces disulfide bond rupture in the gatekeeper with the subsequent DOXO-Gal delivery, which is enzymatically converted by β-gal into the cytotoxic doxorubicin drug, causing cell death. The combined treatment of the pair enzyme/DMSNs-prodrug are more effective in killing cells than the free prodrug DOXO-Gal alone in cells transfected with β-gal.

There is a growing need for non-invasive, cheap, and versatile diagnostic methods and the development of low-cost point-of-care assays constitutes a potential solution. Here, we describe the design of a renal clearable fluorogenic probe (Cy7Gal) which produces a fluorogenic signal readable in the urine. The Cy7Gal probe is applied to the detection of the burden of senescence in several in vivo models. The probe is composed of a dye (Cy7) conjugated with a galactose derivative. Upon administration of the probe in vivo, the up-regulated β-galactosidase enzyme in senescent cells cleaves the O-glycosidic bond in Cy7Gal, releasing the highly emissive Cy7 dye that is renally cleared and measured in unmodified urine by an IVIS imaging system or by a fluorimeter. A good correlation between the burden of senescence and emission in urine is observed. Cy7Gal probe is the first example for the fluorogenic in vivo detection of senescence in urine and may serve as a basis for the development of generalized fluorogenic diagnostic platforms for the easy diagnosis in the urine of different diseases as well as for monitoring therapeutic treatments without the use of expensive equipment or trained personnel.

Cellular senescence is a state of stable cell cycle arrest that can negatively affect the regenerative capacities of tissues and can contribute to inflammation and the progression of various aging-related diseases. Advances in the in vivo detection of cellular senescence are still crucial to monitor the action of senolytic drugs and to assess the early onset or accumulation of senescent cells. Here, we describe a naphthalimide-styrene-based probe (HeckGal) for the detection of cellular senescence both in vitro and in vivo. HeckGal is hydrolyzed by the increased lysosomal β-galactosidase activity of senescent cells, resulting in fluorescence emission. The probe was validated in vitro using normal human fibroblasts and various cancer cell lines undergoing senescence induced by different stress stimuli. Remarkably, HeckGal was also validated in vivo in an orthotopic breast cancer mouse model treated with senescence-inducing chemotherapy and in a renal fibrosis mouse model. In all cases, HeckGal allowed the unambiguous detection of senescence in vitro as well as in tissues and tumors in vivo. This work is expected to provide a potential technology for senescence detection in aged or damaged tissues.

In nature, coordinated communication between different entities enables a group to accomplish sophisticated functionalities that go beyond those carried out by individual agents. The possibility of programming and developing coordinated communication networks at the nanoscale—based on the exchange of chemical messengers—may open new approaches in biomedical and communication areas. Here, a stimulus-responsive circular model of communication between three nanodevices based on enzyme-functionalized Janus Au–mesoporous silica capped nanoparticles is presented. The output in the community of nanoparticles is only observed after a hierarchically programmed flow of chemical information between the members., A community of three nanodevices communicates through a hierarchically programmed circular flow of chemical information between members.

Many important human diseases, and especially cancer, have been related to the overproduction of 8-oxo-7,8-dihydro-2 '-deoxyguanosine (8-oxo-dG). This molecule is a product of oxidative stress processes over nucleophilic bases in DNA. In this work, an aptasensor for the rapid, selective and accurate detection of this oncomarker is presented. The aptasensor consists of a nanoporous anodic alumina material loaded with a dye and is functionalized with an aptamer-based "molecular gate". In the presence of target 8-oxo-dG, the capping aptamer displaces from the surface due to the high affinity of the analyte with the capping aptamer, thus inducing delivery of the preloaded fluorescent dye. In contrast, in the absence of 8-oxo-dG, a poor payload delivery is accomplished. This aptamer-based nanodevice has great sensitivity for 8-oxo-dG, resulting in a LOD of 1 nM and a detection time of ca. 60 min. Moreover, the aptasensor is able to accurately detect 8-oxo-dG in unmodified urine and serum without pre-concentration treatments. This diagnostic tool is validated in a set of 38 urine and serum samples from patients diagnosed of colorectal cancer and control patients. These samples are also analyzed using a standardized and specific ELISA kit. The aptasensor displays excellent sensitivity (95.83/100%) and specificity (80/100%) for 8-oxo-dG detection in serum and urine samples, respectively. Our results may serve as a basis for the development of generalized fluorogenic diagnostic platforms for the easy diagnosis of cancer in biofluids as well as for monitoring therapeutic treatments and detection of relapses without the use of expensive equipment or trained personnel.

[EN] Cellular senescence is a state of stable cell cycle arrest that can negatively affect the regenerative capacities of tissues and can contribute to inflammation and the progression of various aging-related diseases. Advances in the in vivo detection of cellular senescence are still crucial to monitor the action of senolytic drugs and to assess the early onset or accumulation of senescent cells. Here, we describe a naphthalimide-styrene-based probe (HeckGal) for the detection of cellular senescence both in vitro and in vivo. HeckGal is hydrolyzed by the increased lysosomal beta-galactosidase activity of senescent cells, resulting in fluorescence emission. The probe was validated in vitro using normal human fibroblasts and various cancer cell lines undergoing senescence induced by different stress stimuli. Remarkably, HeckGal was also validated in vivo in an orthotopic breast cancer mouse model treated with senescence-inducing chemotherapy and in a renal fibrosis mouse model. In all cases, HeckGal allowed the unambiguous detection of senescence in vitro as well as in tissues and tumors in vivo. This work is expected to provide a potential technology for senescence detection in aged or damaged tissues., R.M. laboratory members thank the financial support from the Spanish Government (project RTI2018-100910-B-C41) and the Generalitat Valenciana (project PROMETEO 2018/024). B.L.-T. is grateful to the Spanish Ministry of Economy for their PhD grants (FPU15/02707). I.G. thanks her contract from IDM. J.F.-B. thanks to his postdoctoral fellowship (CD19/00038). J.A.L.-D. thanks the financial support from the Ministry of Science/MICINN (IJCI-2017-33047). Work in the laboratory of M.S. was funded by the IRB and by grants from the Spanish Ministry of Economy cofunded by the European Regional Development Fund (ERDF) (SAF201348256-R), the European Research Council (ERC-2014-AdG/669622), and the "laCaixa" Foundation. The D.M.-E. laboratory is supported by the Cancer Research U.K. (CRUK), Cambridge Centre Early Detection Programme, by a CRUK Early Detection OHSU project award (C62187/A26989), by a Medical Research Council (MRC) New Investigators Research Grant (NIRG, MR/R000530/1).

[EN] A nanodevice consisted on nanoporous anodic alumina (NAA) supports functionalized with specific and selective antibody-based gatekeepers for the detection of IDH1-R132H mutant enzyme is here reported. Molecular profile and tissue mutations of the tumours (such as IDH1/IDH2 mutations in gliomas) are a great source of information that already make a difference in terms of prognosis and prediction of response to combined therapy. However, standardized methodologies to determine this mutation are time-consuming and cannot provide information before or during surgical intervention, which significantly limits their utility in terms of intraoperative decisionmaking. To solve this limitation, our sensing system, in the presence of the target IDH1-R132H mutant enzyme triggers the delivery of a fluorescent reporter from the antibody-capped NAA that is easily detected using a standard fluorimeter in less than 1 h. Good capabilities of the sensor in terms of sensitivity (limit of detection as low as 0.01 ng/mL) and selectivity are determined. The biosensor is validated in seventeen human glioma tissue samples, also analysed by standardized methodologies, showing significant differences between IDH1 wild-type and IDH1-R132H mutant gliomas (p < 0.01) with high sensitivity, specificity and accuracy (87.5/88.9/88.2) for IDH1-R132H mutational status classification in human glioma tissues. This new detection system might play an important role in surgical interventions, anticipating mutational status information in gliomas and supporting thus decision making and patient survival., This study was supported by the Spanish Government (project RTI2018-100910-B-C41 MCUI/AEI/FEDER, UE), the Generalitat Valenciana (project PROMETEO/2018/024), the Universitat Politecnica de Valencia-Instituto de Investigacion Sanitaria La Fe (GLIOVIEW-IDH and GLIOVIEWIDH_2.0 project) and CIBER-BBN (NANOPATH AND CANDI-EYE projects). S.S. thanks the Instituto de Salud Carlos III and the European Social Fund for the financial support "Sara Borrell" (CD16/000237). L.P. thanks to Ministerio de Economia, Industria y Competitividad for his FPI grant. We also a knowledge service provided by Biobanco La Fe of Instituto de Investigacion Sanitaria La Fe, Val`encia, Spain.