As an emerging technology, photothermal therapy (PTT) has been a strong focus of research in academia in recent years. However, its clinical translation is facing challenge, mainly due to the limitations of the photothermal agents (PTAs) employed. In this domain, there is a pressing need for alternatives PTA with reliable performances for a deep and efficient PTT treatment, together with prominent biocompatibility and high photoacoustic imaging (PAI) response for image-guided PTT in a phototheranostic approach. Heptamethine indocyanines (Cy7.5) dyes are strong candidates due to high absorption capability in the biologically more transparent NIR window, very appealing for PAI/PTT, but demonstrates limited photothermal conversion efficiency and poor resistance to photobleaching. However, these issues could be mitigated through molecular design, as we revealed in the preliminary work, by Cy7.5 C-C covalent dimerization. Concurrently, polymeric micelle (PM)-based drug delivery systems show potential for groundbreaking advances in nanomedicine, yet they are plagued by instability at the nanoscale, which can be addressed through core-crosslinking. Therefore, a combined approach that integrates Cy7.5-dimers with core-crosslinked micelles presents a compelling strategy for developing next-generation PTAs. The CD-Mix project is pioneering this approach, aiming at leveraging Cy7.5-dimerization as an original crosslinking technique to simultaneously achieve nanoscale stability and enhance phototherapeutic efficacy through photo-drug dimerization. To address this challenge, a stepwise methodology will be carried out and will include (i) the synthesis of Cy7.5 with appropriated functional handle to be linked to a polymer, (ii) the synthesis of well-defined amphiphilic and structure-tunable and well-defined Cy7.5-polymer conjugates via efficient macromolecular synthesis combining atom transfer radical polymerization (ATRP), macroinitiator approach and organocatalyzed postpolymerization modification strategies previously developed by the coordinator, (iii) the hydrophobic interactions-driven self-assembling and consecutively the core crosslinking though cyanine dimerization, and finally (iv) the in vitro and on cells properties evaluation, to in the end attain the CD-Mix key concepts and demonstrate the large potential of the Cy7.5-dimers-containg CCPM in biological context. Overall, this ambitious but realistic project is based on the unique expertise of the coordinator than span organic chemistry, polymer chemistry and photophysics and complementarity with his team in colloidal science and photobiology. The realization of the project will greatly benefit both the coordinator, to increase the autonomy and visibility and the host laboratory, to integrates new expertise and contribute to outreach the state of the art in the field and expand its international visibility.

The ChanPulse project is dedicated to the development of an innovative class of molecular photothermal transducers for the controlled translocation of ions and water across lipid bilayers. Building on the discovery of artificial ion and water channels, this project focuses on the implementation of two-photon (2P) activated photothermal transducers as synthetic channels. Unlike conventional approaches, the project emphasizes the direct photoresponsiveness of channel constituents, ensuring precision without compromising the integrity of surrounding cell membranes. Temperature modulation, achieved through photothermy, offers a safe and controlled means to influence cellular functions, with potential therapeutic applications. The primary objectives include the synthesis and photophysical characterization of 2P-activated channels, the assessment of translocation through pulsed photothermal gradients in lipid bilayers, and the rationalization of photo-boosted transport through molecular modeling. The project's novelty lies in the creation of self-photothermal synthetic channels, a breakthrough with potential applications surpassing traditional light-activated molecular switches and photothermal nanoparticles. The ChanPulse project is poised to demonstrate the bottom-up formation of nanochannels and their activation through synergistic photothermal and mass transport processes. The anticipated impact encompasses showcasing the ability of photothermal molecules to enhance translocation, revealing transport mechanisms through adaptive artificial channels, and achieving the first active artificial channel capable of generating heat gradients. The ChanPulse project presents a promising avenue for advancing active transport technologies, with far-reaching implications for therapeutic interventions and technological innovations.

The selective transport of ions and molecules across lipid bilayers is a key process to ensure integrity of living cells and to provide them with advanced functionalities. For instance, natural ion channels can be coupled to a source of energy in order to function out of thermodynamic equilibrium and generate gradients of concentrations (e.g. ATPase Ca2+ pump in the sarcoplasmic reticulum to achieve muscular contraction). Synthetic artificial nanopores have also recently demonstrated remarkable applicative interests for sensing, separation, and delivery processes. However, to the best of our knowledge, the engineering of nanopores capable of functioning out of thermodynamic equilibrium, and possibly capable of generating concentration gradients of ions or molecules, is not yet accessible with the current technologies. The CORNERSTONE project has for objective to equip artificial molecular channels with light-driven rotary motors as transducers in order to regulate selective transport processes across lipid membrane bilayers. It will focus on the out-of-equilibrium mechanical properties of such synthetic nanochannels, with the aim to understand in details their mechanical behavior upon motor rotation, and to control their transport properties in various conditions – possibly against concentration gradients. The rational design and full understanding of these active structures will be implemented along three classes of transporters, i.e. cations, anions, and water channels. The research program in CORNERSTONE will explore the possibilities offered by these new dynamic nanoobjects along 3 work packages including (i) the advanced syntheses of a series of molecular precursors combining various motors and binding hosts for channels formation, (ii) the experimental measurement and rationalization of the transport efficiency across phospholipid bilayers using various assays, and (iii) the precise determination of the motor actuation in relation with the transport mechanism.

Numerous metal complexes display high therapeutic potential and their biological activity is tightly correlated to their reactivity in living systems. Hence, the administered complexes are often pro-drugs that metabolize to active species. However, this metabolization can also be a significant source of toxicity and failure in clinical trials. Therefore, their stability must be screened early during drug development to orient drug design. Drug bio-transformations is typically explored on biological fluids (urine, blood) which does not provide real-time information in living systems. Contrastingly, drug candidates capable to switch their signal after their bio-transformations would be ideal to understand both their in cellulo fate and mode of action, for enabling their rational pharmacomodulation. The OMIC-Fe(II) project aims at developing innovative photoactive tools to simultaneously track the localization of a series of Fe(II)-based drug candidates, and image their bio-transformations, to understand the intricate relationship between their in cellulo fate and bioactivity. Hence, a central “ON/OFF” detector is incorporated in their coordination sphere, and switches its fluorescence upon complexes’ bio-transformations for reporting in real-time on their fate in cellulo.

In an attempt to fight against climate change and global warming, our global carbon footprint must be reduced to a minimum. This incredible challenging objective implies the use of sustainable sources of energy and raw materials, having become an intense focus of research in recent years. In this context, fuel cells are booming again, especially in long-range auto-mobility, since zero CO2 emissions are produced. However, the sustainable and efficient production of hydrogen and oxygen is still an open question and remains a major long-term endeavor. Indeed, most hydrogen is produced from fossil resources such as natural gas or coal, but also from water electrolysis that uses non-renewable electricity. Therefore, there is a clear and urgent need for generating sustainable hydrogen. To tackle this problem, photochemical water splitting offers an incredible possibility of producing hydrogen as well as oxygen from inexhaustible solar energy. Thus, intermittent sunlight would be easily converted into chemical energy carriers for its storage, transportation, and eventual utilization. More importantly, the association of the water-splitting process with that of a fuel cell, producing only water that would be fed back into the water splitting scheme, is undoubtedly a truly sustainable process. Concerning hydrogen evolution, a great deal of photocatalytic materials has been developed, but none of them would allow for large-scale hydrogen production. In the project SunHy, we aim at developing efficient low-cost photoactive systems for photocatalytic proton reduction by mimicking Nature’s approach in leaves. Indeed, we propose exploring solutions based on metalorganic photo-systems bearing only Earth-abundant elements such as iron and cobalt for light-harvesting and redox catalysis, respectively. While the remarkable catalytic properties of cobalt for hydrogen generation have long been demonstrated, iron photosensitizers have been elusive until very recently. Moreover, assemblies bearing base metals have been barely described, and their photophysical and photochemical behavior is still completely unknown. To this end, the consortium of the SunHy project gathers recognized expertise in chemical design and synthesis, and novel Fe/Co heterosystems will be prepared based on the recently achieved breakthroughs of Fe(II) and Fe(III) complexes with extended excited-state lifetimes up to the ns range. Furthermore, expertise regarding characterization techniques together with advanced ultrafast spectroscopy, covering the mid-IR to X-ray domains, will allow not only to understand the working principle of the assemblies but also to improve it upon chemical redesign. Thus, the expected outcome of the SunHy project is a new class of rationally designed photo-catalytic molecules for energy-efficient production of hydrogen to pave the way for long-term large-scale practical applications.