Late diagnosis and difficult treatment represent major obstacles in the fight against cancer. I propose here the development of self-regulated theranostic nanodevices supporting both early cancer diagnosis and targeted, tumor-cell-specific drug-release. Specifically, I will exploit the 'designability' of nucleic acids to design and optimize molecular nanodevices that undergo binding-induced conformational changes upon target binding and, in doing so, signal the presence of a specific tumor marker or release a toxic therapeutic cargo. The inspiration behind my approach is derived from nature, which employs similar nanometer-scale protein and nucleic-acid-based 'switches' as devices to detect –and respond to- specific molecules even against the complex background 'noise' of the physiological environment. Furthering on this 'nature-inspired' synthetic biology view I will also exploit naturally occurring regulatory mechanisms (e.g., allostery, cooperativity, etc.) to tune and edit the dose-response curve of these nanodevices, improve their analytical sensitivity, and optimize drug-release efficiency. In summary, I will use biomimetic 'tricks' taken directly from nature to move beyond the state-of-the-art of sensor design, with the goal being improved diagnostics and 'smarter, ' more effective drug delivery. Achieving these goals will require multidisciplinary expertise in the field of analytical chemistry, biophysics, electrochemistry, bioengineering, computational chemistry and synthetic biology. In my career I have demonstrated skills and expertise in similarly complex projects and in each of these challenging fields. Finally, the development of the proposed nanodevices will significantly impact the safety, compliance and efficacy of therapies and medical procedures bringing to scientific, technological and socio-economic benefits.

Fluid mechanics are fundamental to collective behaviour in nature and technology. Fluids pervade complex systems at every scale, ranging from fish schools and flocking birds to bacterial colonies and nanoparticles for drug delivery. Despite its importance, little is known about the role of fluid mechanics in such applications. Is schooling the result of vortex dynamics synthesised by individual fish wakes or the result of behavioural traits? Is fish schooling energetically favourable? How does blood affect the collective transport of nanoparticles in cancer therapy? We seek to answer these questions through computational methods that resolve the interaction of fluids with multiple, deforming bodies across scales. Our methods rely on the innovative coupling of multi-scale particles with multi-resolution algorithms and grids. Uncertainty quantification techniques will link computations with experimental data. Learning and optimisation algorithms will investigate the optimality of collective behaviour and its relevance to technological applications. Novel, scalable software, engineered to facilitate its broad use, will be made available to the scientific and industrial community. Our group has built strong foundations in computational methods, fluid mechanics, biophysics, nanotechnology and their interfaces and this project gives us the opportunity to reach new frontiers. Our goal is to provide unprecedented information about vortex dynamics of fish schooling, one of the most intriguing patterns in nature. Increased insight will open new horizons for mechanical understanding of collective behaviour, suggest new experiments and contribute to the rational design of industrial applications ranging from robots to wind farms. We will also shed light on mass transport in tumour induced vasculature to enhance the efficacy of drug delivery by nanoparticles, one of the most promising routes for cancer therapy.

Tumor progression is dependent on a number of sequential steps, including initial tumor-vascular interactions and recruitment of blood vessels, as well as an established interaction of tumor cells with their surrounding microenvironment. Failure of a microscopic tumor, either primary, recurrent or metastatic, to complete one or more of these early stages may lead to delayed clinical manifestation of the cancer and a state of stable non-progressing disease. Micrometastasis, dormant tumors, and residual tumor cells contribute to the occurrence of relapse, and constitute fundamental clinical manifestations of tumor dormancy that together are responsible for the vast majority of cancer deaths. However, although the tumor dormancy phenomenon has critical implications for early detection and treatment of cancer, its biology and genetic characteristics are poorly understood. We now propose to investigate the molecular and cellular changes in tumor-host interactions that govern tumor dormancy, which may lead to the discovery of novel tumor dormancy targets and provide tools for dormancy-dependent tumor therapy strategies. In order to achieve this goal, we will integrate the following basic and translational approaches: (i) Establishment of mouse models of dormant and fast-growing tumor pairs; (ii) Functional and molecular characterization of dormant versus fast-growing tumors, (iii) Design of dormancy-promoting tailor-made polymer therapeutics delivering a combination of microRNAs with chemotherapies; (iv) Polymer conjugation to a prodrug designed to be activated by specific enzymes overexpressed in tumors, Turning-ON a near infra-red (NIR) fluorescence signal. When completed, this proposal will shed light on this fundamental cancer biology phenomenon. A better understanding of tumor dormancy and the availability of markers and therapeutic targets will most likely change our perception of tumor progression and, consequently, the way we diagnose and treat the disease.

The use of nanoscience technologies to either perform therapy or diagnosis at the cellular level is expected to revolutionize 21st Century medicine by opening new approaches to cure various illnesses. However, cellular bioengineering is technologically challenging and becomes feasible only when different scientific disciplines are combined together to provide advanced cellular level surgery tools. To this aim, nanosurgery (i.e., surgery on the nanoscale) employs ultrafast laser technology and/or nanoscience emerging technologies (nanophotonics, nano-engineering, plasmonics etc.) to perform cell or even nucleus surgery. The major advantage of the nanosurgery approach is the prospect to disrupt submicrometer-sized organelles within living cells or tissue without affecting the surrounding material or compromising viability of the cell or organism. In this context, we intend to apply and optimize a novel femtosecond laser technique for nanosurgery of cancer cells. The technique, named plasmonic enhanced laser nanosurgery, combines the advantages of two rapidly expanding research and technological fields, namely plasmonics and ultrafast lasers, to build a versatile tool capable of performing high throughput cell nanosurgery. The main innovative goal of the proposal involves optical fiber integration of the plasmonic nanosurgery tool towards in-vivo (i.e. living subject) applications. In-vitro cell transfection (i.e., introduction of siRNA through the membrane of breast cancer stem cells (CSCs)) is the specific nanosurgery application of the Light2NanoGene project. The latter, is driven by the remarkable ability of these undifferentiated cells within a tumor to self-renew and promote metastases. The successful transfection of the CSCs with siRNA will silence the expression of key genes involved in their aggressive behavior. We expect proof-of-concept elimination of their capacity for self-regeneration and induction of metastases.

This project is designed to provide answers to questions not yet covered in the literature regarding hyperthermia cancer therapy based on the activation of magnetic and/or plasmonic nanomaterials. It aims at understanding and measuring nanoparticle-based heat-generating potential in environments that gradually approach the in vivo situation. The originality of the approach proposed is to combine in-depth physical studies (magnetic, plasmonic) of nanomaterials in biological environment while exploring new therapeutic modalities. Two main issues will be addressed: (1) the influence of magnetic or plasmonic nanoparticle confinement inside cells on heat-generating potential; (2) the possible synergism between magnetic and plasmonic hyperthermia, with a view to combined therapy, and their cumulative efficacy in solution, in vitro cell models, and in vivo tumour models. These issues will be addressed at several levels, ranging from materials chemistry to antitumoral applications in living animals, by exploiting multiple disciplines. To open the way to new therapeutic tools, it will be necessary to test a wide variety of nanoparticles with different compositions, shapes and sizes, provided by leading teams in nanomaterials synthesis, as well as to develop appropriate nanometrologic methods to detect, quantify and characterize the different nanostructures in their biological environment.

Supported metal nanoparticles are used as catalysts to accelerate and steer chemical conversions to produce, e.g., transportation fuels, chemicals and medicines. Albeit of eminent importance, supported metal catalysts are almost exclusively synthesized in liquid-phase processes that are often considered 'an art rather than a science'. Although recent results from our laboratory and others on the fundamentals of catalysts synthesis have led to many new insights, the lack of methodology to investigate directly the formation of supported nanoparticles in the liquid phase hampers progress. The key objective of this proposal is to image and thereby obtain a detailed understanding of both the genesis (synthesis) and the dynamics (catalysis) of supported metal nanoparticles in the liquid phase with nanometer resolution and in real time. To this end we will combine two recent developments: (1) a liquid-phase in situ cell for use in a transmission electron microscope (TEM) with (2) the element specificity of a Chemi-STEM that provides element specific images with nanometer resolution.. In this way we will image in the liquid phase the nucleation and growth of nanoparticles on a support. As support we plan to use materials with ordered porosity that allow imaging of genesis of nanoparticles in liquid confined in nanopores. The key objective of this proposal will be addressed in four projects (1) acquisition and implementation of a liquid-phase cell within a Chemi-STEM which is then used to study (2) ion adsorption of noble metal complexes onto silica and zeolites followed by liquid-phase reduction to form metallic nanoparticles, (3) crystallization of metal nitrates in nanopores of silica and carbon, (4) dynamics of palladium nanoparticles in liquid-phase catalysis. The new insights will move catalysts synthesis 'from art to science' and provide control over the properties of supported nanoparticles to arrive at novel catalysts for sustainable processes.

SNAL is a multidisciplinary programme specially designed to provide scientific and transferable skill training and career development for early stage researchers and experienced researchers in membrane research. Working in a multidisciplinary network will give the researchers a broad perspective on their research field as well as the basic ability of pursuing a research project from basic sciences to industrial applications. The broad aim is to train a new cohort of researchers with systemic thinking equipped with generic skills in combining experimental studies and computer simulations to prepare them for fruitful careers in academia and industry. One challenge for the project is the design and synthesis of novel biomaterials able to modify membrane properties. This requires deep understanding of the interactions of lipid membranes with nano-objects including functional biomimetic polymers, polymeric micelles, carbon nanotubes and polymer therapeutic complexes/conjugates to enable the intelligent design of novel materials with improved bilayer modifying properties. To achieve this goal we have assembled a highly interdisciplinary team of leading groups all having synergies in their established research interests in the field of lipid bilayer -nano-objects interactions. The project combines computer simulations, chemical synthesis, clinical and industrial expertise, physical and biological experiments. The industry involvement in the project is very high with full participation of Unilever and Biopharma, the companies from different sectors. Complementarity of partner skills provides a logical basis for a collective training programme. The full cycle of the design process, from theoretical models to synthesis and experimental and clinical validation, is of particular importance for training of ESRs and their future career development.

We propose to develop and apply novel methods of nonlinear spectroscopy to investigate the significance and consequences of coherent effects for a variety of photophysical and photochemical molecular processes. We will use coherent two-dimensional (2D) spectroscopy as an ideal tool to study electronic coherences. Quantum mechanics as described by the Schrödinger equation is fully coherent: The phase of a wavefunction evolves deterministically in the time-dependent case. However, observations are restricted to reduced 'systems' coupled to an 'environment.' The resulting transition from coherent to incoherent behavior on an ultrafast timescale has many yet unexplored consequences, e.g. for transport in photosynthesis, photovoltaics or other molecular 'nanomaterials.' In contrast to conventional 2D spectroscopy, we will not measure the coherently emitted field within a four-wave mixing process but rather implement a range of incoherent observables (ion mass spectra, fluorescence, and photoelectrons). Yet we can still extract all the desired information using 'phase cycling' with collinear pulse sequences from a femtosecond pulse shaper. This opens up a new range of interdisciplinary experiments and will allow for the first time a direct nonlinear-spectroscopic comparison of molecular systems in all states of matter. Specifically, we will realize 2D spectroscopy in molecular beams, liquids, low-temperature solids, and on surfaces including heterogeneous and nanostructured samples. Tuning the external couplings will help elucidating the role of the environment in electronic (de)coherence phenomena. Furthermore, we will combine 2D spectroscopy with subdiffraction spatial resolution using photoemission electron microscopy (PEEM). This enables us to map transport in molecular aggregates and other heterogeneous nanosystems in time and space on a nanometer length scale. Thus we access the intersection between the domains of electronics and nanophotonics.

In this project, we will control photonic nanostructures by external feedback, optical injection and synchronization. This will allow us to study nonlinear dynamics in quantum systems and to externally manipulate and stabilize light-matter interaction in the regime of quantum electrodynamics (cQED). We will experimentally and theoretically address a) optical injection and feedback control of quantum dot (QD)–microlasers, b) quantum control cQED systems via delayed single photon feedback, and c) mutually coupled and synchronized chaotic microcavity systems. In a) we will advance the concepts of time-delayed coupling in standard semiconductor laser diodes to few photon states, where quantum fluctuations contribute to or even dominate over the usual classical dynamics. Feedback-coupling in microlasers will allow us to explore the limits of a classical description of chaotic laser dynamics via the Lang-Kobayashi rate equations and to develop an advanced model taking cQED- and QD-specific effects into account. This subject will be complemented by the study of optical injection of coherent light and non-classical light into microlasers to influence and study mode-locking, chaos and stimulated emission down to the quantum level. Single photon feedback in b) will be applied to stabilize coherent coupling of light and matter and to act against decoherence which constitutes a major bottleneck for application of semiconductor nanostructures in quantum information technology. In c) the mutual coupling of microlasers will be used to study synchronization of chaotic quantum devices at the single photon limit and to explore the underlying physics of isochronal synchronization. Our work will have important impact at an interdisciplinary level on the development of nonlinear dynamical systems towards the quantum limit and the understanding of fundamental light-matter interaction in the presence of time delayed single photon feedback.

In InanoMOF, we aim to develop frontier Supramolecular and Nanochemistry methodologies for the synthesis of a novel class of structures via controlled assembly of nanoscale metal-organic frameworks (nanoMOFs) and inorganic nanoparticles (INPs). These methods will embody the premise that 'controlled object-by-object nano-assembly is a ground-breaking approach to explore for producing systems of higher complexity with advanced functions'. The resulting hybrid nanoMOF@INPs will marry the unique properties of INPs (magnetism of iron oxide NPs and optics of Au NPs) to the functional porosity of MOFs. The first part of InanoMOF encompasses the design, synthesis-assembly and characterisation of nanoMOF@INPs - advanced MOF-based sorbents that incorporate the functionality of the INPs used: magnetically controlled movement, in vivo detectability, enhanced biocompatibility and porosity, pollutant removal, or controlled sorption/delivery. The second part of InanoMOF entails studying the physicochemical properties of the synthesised nanoMOF@INPs and ascertaining their utility as drug-delivery/theranostic systems and as magnetic sorbents for pollutant removal. Specifically, we will study their stability in working media and determine their capacities for drug or pollutant sorption/delivery capacities. As proof-of-concept, we will study their toxicity in vitro and in vivo; enhancement of their in vitro therapeutic efficacy; and their capacity to remove pollutants (in real water and gasoline/diesel fuel samples) via magnetic assistance. In InanoMOF we will endeavour to establish the synthetic bases for controlling the spatial ordering of nanoMOF crystals, whether alone or combined with other nanomaterials (e.g. INPs, graphene, etc.). We are confident that our work will ultimately enable researchers to create MOF-based composites having cooperative and synergistic properties and functions for myriad applications (e.g. heterogeneous catalysis, sensing and separation).