Enzyme-functionalized hybrid mesoporous nanodevices for sensing, controlled release and molecular communication

Tesis por compendio[ES] La presente tesis doctoral titulada "Nanodispositivos mesoporosos híbridos funcionalizados con enzimas para detección, liberación controlada y comunicación molecular" se centra en el diseño, preparación, caracterización y evaluación de distintos nanodispositivos híbridos orgánico-inorgánicos utilizando como soporte nanopartículas tipo Janus de oro y sílice mesoporosa, que se equipan con enzimas, especies fluorescentes y puertas moleculares. Como conclusión general, los estudios realizados muestran que la incorporación de enzimas sobre nanopartículas permite introducir funciones de reconocimiento con alta especificidad y diseñar nanodispositivos avanzados para distintas finalidades. La combinación de nanopartículas híbridas con grupos orgánicos como puertas moleculares, efectores enzimáticos y especies cromo- fluorogénicas o fármacos puede resultar muy versátil; y se espera que los resultados obtenidos puedan inspirar el desarrollo de nuevos materiales inteligentes con aplicación en distintas áreas como la nanomedicina y la detección de moléculas de interés.[CA] La present tesi doctoral titulada "Nanodispositius mesoporosos híbrids funcionalitzats amb enzims per a detecció, alliberació controlada i comunicació molecular" es centra en el disseny, preparació, caracterització i avaluació de distints nanodispositius híbrids orgànic-inorgànics utilitzant com a suport nanopartícules tipus Janus d'or i sílice mesoporosa, que s'equipen amb enzims, espècies fluorescents i portes moleculars. Com a conclusió general, els estudis realitzats mostren que la incorporació d'enzims sobre nanopartícules permeten introduir funcions de reconeixement amb alta especificitat i dissenyar nanodispositius avançats per a distintes finalitats. La combinació de nanopartícules híbrides amb grups orgànics com portes moleculars, efectors enzimàtics i espècies cromo-fluorogèniques o fàrmacs pot resultar molt versàtil; i s'espera que els resultats obsessos inspiren el desenvolupament de nous materials intel·ligents amb aplicació en distintes àrees com la nanomedicina i la detecció de molècules d'interés.[EN] This PhD thesis entitled "Enzyme-functionalized hybrid mesoporous nanodevices for sensing, controlled release and molecular communication" is focused on the design, synthesis, characterization and evaluation of several hybrid organic-inorganic nanodevices using Janus gold-mesoporous silica nanoparticles as scaffolds, equipped with enzymes, fluorescent species and molecular gates. In conclusion, these studies show that the incorporation of enzymes on nanoparticles allows to introduce recognition capabilities with high specificity and to design advanced nanodevices for different purposes. The combination of hybrid nanoparticles with organic groups such as molecular gates, enzymatic effectors and chromo-fluorogenic species or drugs can be very versatile; and we hope that the obtained results inspire the development of new smart materials with application in different areas such as nanomedice and sensing.Llopis Lorente, A. (2019). Enzyme-functionalized hybrid mesoporous nanodevices for sensing, controlled release and molecular communication [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/117612TESISCompendi

Chemical Cascading Between Polymersomal Nanoreactor Populations

[EN] Harnessing interactions of functional nano-compartments to generate larger particle assemblies allows studying diverse biological behaviors based on their population states and can lead to the development of smart materials. Herein, thiol-functionalized polymersome nanoreactors are utilized as responsive organelle-like nano-compartments-with inherent capacity to associate into larger aggregates in response to change in the redox state of their environment-to study the kinetics of cascade reactions and explore functions of their collective under different population states. Two nanoreactor populations, glucose oxidase- and horseradish peroxidase-loaded polymersomes, are prepared, and the results of their cascading upon addition of glucose are investigated. The kinetics of resorufin production in associated polymersomes and non-associated polymersome populations are compared, observing a decreased rate upon association. For the associated populations, faster chemical cascading is found when the two types of nanoreactors are associated in a concerted step, as compared to sequential association. The addition of competing agents such as catalase impacts the communication between non-associated polymersomes, whereas such an effect is less pronounced for the associated ones. Altogether, the results showcase the impact of collective associations on enzymatic cascading between organelle-like nanoreactors.Y.A. and A.L.-L. contributed equally to this work. The authors would like to acknowledge the support from the Dutch Ministry of Education, Culture, and Science (Gravitation program 024.001.035 and Spinoza premium) and the ERC Advanced Grant (Artisym 694120).A.L.-L. acknowledges support from the MSCA Cofund project oLife, which has received funding from the European Union's Horizon 2020 research and innovation program under the Grant Agreement 847675; and the Maria Zambrano Program from the Spanish Government funded by NextGenerationEU from the European Union. Dr. Imke Pijpers is thanked for cryo-TEM imaging. Dr. Pascal Welzen is acknowledged for advice and useful discussion on polymer and polymersome preparation.Altay, Y.; Llopis-Lorente, A.; Abdelmohsen, LKEA.; Van Hest, JC. (2023). Chemical Cascading Between Polymersomal Nanoreactor Populations. Macromolecular Chemistry and Physics. 224(1):1-5. https://doi.org/10.1002/macp.20220026915224

A Versatile New Paradigm for the Design of Optical Nanosensors Based on Enzyme-Mediated Detachment of Labeled Reporters: The Example of Urea Detection

"This is the peer reviewed version of the following article: Llopis-Lorente, Antoni, Reynaldo Villalonga, M. Dolores Marcos, Ramón Martínez-Máñez, and Félix Sancenón. 2018. A Versatile New Paradigm for the Design of Optical Nanosensors Based on Enzyme‐Mediated Detachment of Labeled Reporters: The Example of Urea Detection. Chemistry A European Journal 25 (14). Wiley: 3575 81. doi:10.1002/chem.201804706. , which has been published in final form at https://doi.org/10.1002/chem.201804706. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving."[EN] Here, a new bio-inspired nanoarchitectonics approach for the design of optical probes is presented. It is based on nanodevices that combine 1) an enzymatic receptor subunit, 2) a signaling subunit (consisting of a labeled reporter attached to a silica surface), and 3) a mechanism of communication between the two sites based on the production of chemical messengers by the enzymatic subunit, which induces the detachment of the reporter molecules from the silica surface. As a proof of concept, a urea nanosensor based on the release of Alexa-Fluor-647-labeled oligonucleotide from enzyme-functionalized Janus gold-mesoporous-silica nanoparticles (Au-MSNPs) was developed. The Janus particles were functionalized on the silica face with amino groups to which the labeled oligonucleotides were attached by electrostatic interactions, whereas the gold face was used for grafting urease enzymes. The nanodevice was able to release the fluorescent oligonucleotide through the enzyme-mediated hydrolysis of urea to ammonia and the subsequent deprotonation of amino groups on the silica face. This simple nanodevice was applied for the fluorometric detection of urea in real human blood samples and for the identification of adulterated milk. Given the large variety of enzymes and reporter species that could be combined, this is a general new paradigm that could be applied to the design of a number of optical probes for the detection of target analytes.A.L.-L. is grateful to "La Caixa" Banking Foundation for his Ph.D. fellowship. The authors thank to the Spanish Government (MINECO Projects MAT2015-64139-C4-1, AGL2015-70235-C2-2-R, CTQ2014-58989-P and CTQ2015-71936-REDT) and the Generalitat Valencia (Projects PROMETEOII/2014/047, PROMETEO2018/024) for support. The Comunidad de Madrid (S2013/MIT-3029, Programme NANOAVANSENS) is also gratefully acknowledged.Llopis-Lorente, A.; Villalonga, R.; Marcos Martínez, MD.; Martínez-Máñez, R.; Sancenón Galarza, F. (2019). A Versatile New Paradigm for the Design of Optical Nanosensors Based on Enzyme-Mediated Detachment of Labeled Reporters: The Example of Urea Detection. Chemistry - A European Journal. 25(14):3575-3581. https://doi.org/10.1002/chem.201804706S35753581251

Mesoporous silica materials for controlled delivery based on enzymes

[EN] This review summarises examples of capped mesoporous silica materials for controlled delivery that use enzymes as external triggers or functional components of the gating ensemble.Financial support from the Spanish Government and FEDER funds (Project MAT2015-64139-C4-1) and the Generalitat Valencia (Project PROMETEOII/2014/047) is gratefully acknowledged. A. Llopis-Lorente is grateful to "La Caixa'' Banking Foundation for his PhD fellowship. B. Lozano-Torres is grateful to the Spanish Ministry of Economy and Competitiveness (MEC) for her FPU grant. Also A. Bernardos thanks the Spanish MEC for her Juan de la Cierva Contract.Llopis-Lorente, A.; Lozano-Torres, B.; Bernardos Bau, A.; Martínez-Máñez, R.; Sancenón Galarza, F. (2017). Mesoporous silica materials for controlled delivery based on enzymes. Journal of Materials Chemistry B. 5(17):3069-3083. https://doi.org/10.1039/C7TB00348JS3069308351

Confined Motion: Motility of Active Microparticles in Cell-Sized Lipid Vesicles

[EN] Active materials can transduce external energy into kinetic energy at the nano and micron length scales. This unique feature has sparked much research, which ranges from achieving fundamental understanding of their motility to the assessment of potential applications. Traditionally, motility is studied as a function of internal features such as particle topology, while external parameters such as energy source are assessed mainly in bulk. However, in real-life applications, confinement plays a crucial role in determining the type of motion active particles can adapt. This feature has been however surprisingly underexplored experimentally. Here, we showcase a tunable experimental platform to gain an insight into the dynamics of active particles in environments with restricted 3D topology. Particularly, we examined the autonomous motion of coacervate micromotors confined in giant unilamellar vesicles (GUVs) spanning 10¿50 ¿m in diameter and varied parameters including fuel and micromotor concentration. We observed anomalous diffusion upon confinement, leading to decreased motility, which was more pronounced in smaller compartments. The results indicate that the theoretically predicted hydrodynamic effect dominates the motion mechanism within this platform. Our study provides a versatile approach to understand the behavior of active matter under controlled, compartmentalized conditions.The authors would like to acknowledge the support from the Dutch Ministry of Education, Culture and Science (Gravitation program 024.001.035 and Spinoza premium) and the ERC Advanced Grant (Artisym 694120) . A.L.-L. acknowledges the support from the MSCA Cofund Project of Life, which has received funding from the European Union's Horizon 2020 research and innovation program under the grant agreement 847675, and the Maria Zambrano Program from the Spanish Government funded by NextGenerationEU from the European Union. Dr. Bastiaan Buddingh is thanked for useful discussions regarding GUV preparation and handling. Dr. Shoupeng Cao is thanked for providing the azido-functionalized block polymer. We specially thank Prof. Samuel Sanchez for the tailor-made particle-tracking software based on Python.Song, S.; Llopis-Lorente, A.; Mason, AF.; Abdelmohsen, LK.; Van Hest, JCM. (2022). Confined Motion: Motility of Active Microparticles in Cell-Sized Lipid Vesicles. Journal of the American Chemical Society. 144:13831-13838. https://doi.org/10.1021/jacs.2c05232138311383814

Selective and sensitive colorimetric detection of the neurotransmitter serotonin based on the aggregation of bifunctionalised gold nanoparticles

[EN] We report a simple, sensitive and selective method for the colorimetric detection of serotonin (5-HT) in aqueous media using bifunctionalized gold nanoparticles (AuNPs). The probe (1) consisted of AuNPs functionalised with dithiobis(succinimidylpropionate) (DSP) and N-acetyl-l-cysteine (NALC). DSP was chosen to react with the amino group of 5-HT, whereas NALC was chosen to bind the hydroxyl group in 5-HT through hydrogen bonding and electrostatic interactions. A double interaction between nanoparticles and the hydroxyl and the amino group of serotonin led to interparticle-crosslinking aggregation. This, resulted in a colour change from red to blue that can be observed by the naked eye. The probe was selective to 5-HT and no colour modulation was observed in the presence of other neurotransmitters (i.e. dopamine, epinephrine, norepinephrine), selected biomolecules (i.e. L-tyrosine, gamma-aminobutyric acid, L-cysteine, uric acid, oxalic acid, aspartic acid and glutamic acid) and common inorganic species. A limit of detection as low as 0.1 mu M was determined in buffered water at pH 7 by UV-vis titrations. Similar response of the probe to 5-HT was observed in simulated blood serum, with a limit of detection of 0.12 mu M, and a linear response within the 0-3 mu M concentration range, which is within the range of the 5-HT concentrations of clinical interest. Finally, the performance of probe (1) in real human blood samples was evaluated, and showed a remarkable ability to distinguish between normal 5-HT levels and 5-HT levels indicative of disease. (c) 2017 Elsevier B.V. All rights reserved.Financial support from the Spanish Government (Projects MAT2015-64139-C4-1-R and MAT2015-64139-C4-4-R) and the Generalitat Valenciana (Project PROMETEOII/2014/047) is gratefully acknowledged. T. Godoy-Reyes is grateful to the Generalitat Valenciana for her Santiago Grisolia fellowship. A. Llopis-Lorente thanks "La Caixa" Banking Foundation for his PhD grant. SCSIE (Universitat de Valencia) is gratefully acknowledged for all the equipment employed. NMR was registered at the U26 facility of ICTS "NANBIOSIS" at the Universitat de Valencia. Support from the Juana Portaceli Health Centre of the Universitat Politecnica de Valencia to obtain blood samples from a healthy volunteer is gratefully acknowledged.Godoy-Reyes, TM.; Llopis-Lorente, A.; Costero, AM.; Sancenón, F.; Gaviña, P.; Martínez-Máñez, R. (2018). Selective and sensitive colorimetric detection of the neurotransmitter serotonin based on the aggregation of bifunctionalised gold nanoparticles. Sensors and Actuators B Chemical. 258:829-835. https://doi.org/10.1016/j.snb.2017.11.181S82983525

Ultrafast Directional Janus Pt-Mesoporous Silica Nanomotors for Smart Drug Delivery

[EN] Development of bioinspired nanomachines with an efficient propulsion and cargo-towing has attracted much attention in the last years due to their potential biosensing, diagnostics, and therapeutics applications. In this context, self-propelled synthetic nanomotors are promising carriers for intelligent and controlled release of therapeutic payloads. However, the implementation of this technology in real biomedical applications is still facing several challenges. Herein, we report the design, synthesis, and characterization of innovative multifunctional gated platinum¿mesoporous silica nanomotors constituted of a propelling element (platinum nanodendrite face), a drug-loaded nanocontainer (mesoporous silica nanoparticle face), and a disulfide-containing oligo(ethylene glycol) chain (S¿S¿PEG) as a gating system. These Janus-type nanomotors present an ultrafast self-propelled motion due to the catalytic decomposition of low concentrations of hydrogen peroxide. Likewise, nanomotors exhibit a directional movement, which drives the engines toward biological targets, THP-1 cancer cells, as demonstrated using a microchip device that mimics penetration from capillary to postcapillary vessels. This fast and directional displacement facilitates the rapid cellular internalization and the on-demand specific release of a cytotoxic drug into the cytosol, due to the reduction of the disulfide bonds of the capping ensemble by intracellular glutathione levels. In the microchip device and in the absence of fuel, nanomotors are neither able to move directionally nor reach cancer cells and deliver their cargo, revealing that the fuel is required to get into inaccessible areas and to enhance nanoparticle internalization and drug release. Our proposed nanosystem shows many of the suitable characteristics for ideal biomedical destined nanomotors, such as rapid autonomous motion, versatility, and stimuli-responsive controlled drug release.The authors want to thank the Spanish Government for RTI2018-100910-B-C41 (MCIU/AEI/FEDER, UE) and CTQ2017-87954-P projects and the Generalitat Valenciana for support by project PROMETEO/2018/024. P.D. thanks the Spanish government for her Juan de la Cierva postdoctoral fellowship. E.L.-S. thanks MINECO for her FPU fellowship. A.E. is also grateful for her Ph.D. grant by the Generalitat Valenciana.Diez-Sánchez, P.; Lucena-Sánchez, E.; Escudero-Noguera, A.; Llopis-Lorente, A.; Villalonga, R.; Martínez-Máñez, R. (2021). Ultrafast Directional Janus Pt-Mesoporous Silica Nanomotors for Smart Drug Delivery. ACS Nano. 15(3):4467-4480. https://doi.org/10.1021/acsnano.0c084044467448015

A 1-to-2 demultiplexer hybrid nanocarrier for cargo delivery and activation

[EN] A biocomputing strategy implemented in hybrid nanocarriers for controlled cargo delivery is described. The nanodevice consists of enzyme-functionalized Janus Au-mesoporous silica nanoparticles, which behave as an electronic demultiplexer (DEMUX). The nanocarrier is capable of reading molecular information from the environment (lactose) and selecting one of two possible outputs (galactose production or 4-methylumbellilferone release and activation) depending on the presence of an addressing input NAD(+).The authors wish to thank the Spanish Government (projects RTI2018-100910-B-C41 (MCUI/AEI/FEDER, UE), CTQ2017-87954-P), the Generalitat Valenciana (PROMETEO 2018/024), the Comunidad de Madrid (IND2017/BMD-7642) and CIBER-BBN (NANOCOMMUNITY project) for support.De Luis-Fernández, B.; García-Fernández, A.; Llopis-Lorente, A.; Villalonga, R.; Sancenón Galarza, F.; Martínez-Máñez, R. (2020). A 1-to-2 demultiplexer hybrid nanocarrier for cargo delivery and activation. 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Acetylcholine-responsive cargo release using acetylcholinesterase-capped nanomaterials

[EN] Mesoporous silica nanoparticles capped with acetylcholinesterase, through boronic ester linkages, selectively release an entrapped cargo in the presence of acetylcholine.The authors acknowledge financial support from the Spanish Government (MAT2015-64139-C4-1-R, MAT2015-64139-C4-4-R and AGL2015-70235-C2-2-R) and the Generalitat Valenciana (PROMETEO2018/024). T. Godoy-Reyes is grateful to Generalitat Valenciana for her Santiago Grisollía fellowship. A. García-Fernández is grateful to the Spanish Government for her FPU fellowshipGodoy-Reyes, TM.; Llopis-Lorente, A.; García-Fernández, A.; Gaviña, P.; Costero, AM.; Martínez-Máñez, R.; Sancenón Galarza, F. (2019). Acetylcholine-responsive cargo release using acetylcholinesterase-capped nanomaterials. Chemical Communications. 55(41):5785-5788. https://doi.org/10.1039/c9cc02602aS578557885541McCorry, L. K. (2007). Physiology of the Autonomic Nervous System. American Journal of Pharmaceutical Education, 71(4), 78. doi:10.5688/aj710478W. 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Hybrid Mesoporous Nanocarriers Act by Processing Logic Tasks: Toward the Design of Nanobots Capable of Reading Information from the Environment

[EN] Here, we present the design of smart nano-devices capable of reading molecular information from the environment and acting accordingly by processing Boolean logic tasks. As proof of concept, we prepared Au-mesoporous silica (MS) nanoparticles functionalized with the enzyme glucose dehydrogenase (GDH) on the Au surface and with supramolecular nanovalves as caps on the MS surface, which is loaded with a cargo (dye or drug). The nanodevice acts as an AND logic gate and reads information from the solution (presence of glucose and nicotinamide adenine dinucleotide (NADI), which results in cargo release. We show the possibility of coimmobilizing GDH and the enzyme urease on nanoparticles to mimic an INHIBIT logic gate, in which the AND gate is switched off by the presence of urea. We also show that such nanodevices can deliver cytotoxic drugs in cancer cells by recognizing intracellular NAD(+) and the presence of glucose.A.L.-L. is grateful to "La Caixa" Banking Foundation for his Ph.D. grant. A.G.-F. and B.de L. thank the Spanish government for FPU fellowships. The authors are grateful to the Spanish Government (MINECO Projects MAT2015-64139-C4-1, CTQ2014-58989-P, and CTQ2015-71936-REDT) and the Generalitat Valencia (Project PROMETEOII/2014/047 and PROMETEOII/2014/061) for support. The Comunidad de Madrid (S2013/MIT-3029, Programme NANOAVANSENS) is also gratefully acknowledged.Llopis-Lorente, A.; De Luis-Fernández, B.; García-Fernández, A.; Jiménez-Falcao, S.; Orzaez, M.; Sancenón Galarza, F.; Villalonga, R.... (2018). Hybrid Mesoporous Nanocarriers Act by Processing Logic Tasks: Toward the Design of Nanobots Capable of Reading Information from the Environment. ACS Applied Materials & Interfaces. 10(31):26494-26500. https://doi.org/10.1021/acsami.8b05920S2649426500103