Various domains require materials that integrate emerging properties with multifunctionality to efficiently solve complex issues (e.g. early detection and treatment of severe pathologies, sensing and correction of food quality issues, simultaneous determination of the presence of pollutants in water, biofilm formation). Amongst the most promising strategies is the use of bio-inspired bottom-up approaches based on interfacing biomolecules (enzymes, proteins, DNA) with synthetic assemblies (micelles, vesicles, particles). This combination can produce bio-synthetic materials that surpass conventional systems in terms of efficacy and functionality as they profit from the activity and specificity of the biomolecules whilst the synthetic matrix provides the necessary stability and robustness. The objective of this project is to create bio-inspired multifunctional supramolecular assemblies , in which activation and responses are stimuli-triggered. These multifunctional supramolecular assemblies will serve either as multiplexed reaction spaces at the nanoscale with magnetic controlled propulsion or as active surfaces patterned with responsive nano- assemblies. These directions, connected by biomolecules serving as active components, are inspired by aspects of natural organelles and cells, including signalling pathways, responsiveness and triggered production of molecules. Overall, this interdisciplinary project combines physical chemistry, nanoscience, surface science and enzyme biochemistry. The first subproject plan is to create clusters of active Janus-multicompartments by DNA-mediated self-organization of magnetic Janus nanoparticles and catalytic compartments based on polymersomes equipped with active molecules. Two different types of catalytic nanocompartment will be specifically attached to the lobes of Janus nanoparticles and activated by stimuli present in the environment. The intrinsic activity of the encapsulated molecules inside the catalytic nanocompartments will induce multifunctionality into the clusters, whilst the Janus nanoparticles will serve as "shuttles" to support the directional propulsion of the clusters in the presence of a magnetic field. To demonstrate the potential of the system in photodynamic therapy, we have selected enzymes and photosensitizers, respectively, as model compounds inside each type of catalytic nanocompartments. Clusters of active Janus-multicompartments have the advantages of segregation of protected spaces for active molecules and dual functionality with time, and space precision due to the stimuli-responsive manner of their activation and propulsion. The second subproject aims to construct multifunc tional "active surfaces" by specific immobilization of different types of biomolecule-loaded nano-assembly (peptide nanoparticles and polymersomes) on solid supports. These active surfaces will exhibit dual functionality in the presence of stimuli: polymersomes containing enzymes will act as catalytic nanocompartments for sensing pH changes, whilst peptide nanoparticles will release their cargo upon changes in temperature. A controlled surface pattern will be achieved by combining two approaches for immobilization of nano- assemblies on solid supports: DNA-mediated connection for polymersomes and covalent binding for peptide nanoparticles. To illustrate one of the possible applications, we have selected enzymes and flavonoids for sensing and correcting early changes in food quality. Such active surfaces have several advantages including versatility and modularity of specific patterning and multifunctionality associated with simultaneous responses to external stimuli. Knowledge gained from the fundamental study of the molecular factors, interactions and conditions that are essential to build such multifunctional bio-synthetic assemblies will support their development as efficient platform for solving complex issues in various fields, including medicine, food science, environmental sciences, and technology.

The aim of this interdisciplinary project is to develop next generation functional synthetic compartments whose composition is controlled by special transmembrane proteins that deliver or selectively let molecules pass to the interior, and to test their activity in vitro . By inserting distinct membrane proteins in the synthetic membrane of compartments we plan to deliver proteins to the compartment interior or to allow a specific molecular flow across the membrane.

The innovative microfluidic screening platform μDIVA will allow direct discovery of neutralizing antibodies against viral infections and thus shorten the drug development process. It will be benchmarked with the current pandemic SARS-CoV-2 and applied to the discovery of CMV-neutralizing antibodies.

The objective of SINPFood is to develop reliable characterization techniques for the detection of synthetic silicon oxide nanoparticles in model of complex matrixes mimicking nutritional products and in selected nutritional products, followed by cytotoxicity assays of such nanoparticles in combination with components of food products.

The objective of the project is to facilitate clinical application of the unique drug platform developed by TargImmune Therapeutics, cancer-targeted nanoparticles activating immune system, by better understanding its mode of action as well as thorough characterization of nanoparticle physicochemical properties

Molecular Systems Engineering is a National Centre of Competence in Research (NCCR) funded by the Swiss National Science Foundation (SNSF), and headed by the University of Basel and the ETH Zurich. This NCCR combines expertise from chemistry, biology, physics, bioinformatics, and engineering. The overreaching aim is to develop tools and devices to monitor and manipulate off-equilibrium (bio)chemical systems. These may find applications in the synthesis of high added-value products, as innovative diagnostic tools and for the restoration of a desired cellular or organ function.

This project will develop an innovative methodology to create size controlled polymer clusters of compartments that selectively and stably attach to the surface of epithelial cells. Such compartment clusters will be used to attach to scavenger receptors of the cell membranes and support medical applications. By loading specific compartments with different compounds and them zipping them together, the clusters will achieve multifunctionality serving for the development of nanoteranostics and dual-sensing systems. In addition, such segregated confined spaces at the nanoscale can be used to achieve efficient complex cascade reactions in between compartments.

Our motivation is to overcome key shortcomings of current GPCR lab-on-a-chip nanoscale drug discovery and extend the established and well accepted but limited SPR-based drug screening by new possibilities to address inherently difficult-to-screen GPCRs, and more than that, to obtain detailed functional information about differences of ligands at nanoscale and the biological effects that they trigger for more comprehensive drug profiling. In fact, the need to identify drugs that discriminate between G protein and arrestin signaling has revolutionized GPCR drug discovery setting paradigm shifts and defining "biased agonism" or "functional selectivity". Investment-intense activities can be observed in terms of patent disclosures for new chemical entities with such properties by Biotech, but also large Pharma companies. NanoGhip finds application not only in lab-on-a-chip nanoscale drug screening, but also assists struc-ture-based drug discovery (SBDD), e.g. for determination of ideal crystallization conditions. Of course, NanoGhip could be as well implemented in diagnostic lab-on-a-chip tools to detected overregulated na-tive ligands as indicators of disease on-site.

The development of new functional materials by bottom-up approaches that combine different building blocks at the nanoscale in a novel architecture with improved or new properties and functionality is currently in focus for applications in various domains. One of the most promising strategies is to interface biomolecules (enzymes, proteins, DNA, biomimics) with synthetic assemblies that have a variety of architectures (micelles, vesicles, tubes, particles) in order to mimic natural structures and functions. Such bio-hybrid materials have the advantages of combining the activity and specificity of biomolecules with the stability and precise topology of a synthetic matrix, and thus underscore conventional systems in terms of efficacy and functionality. This project aims to develop functional protein-polymer assemblies, which will serve as new types of catalytic nanocompartments providing efficient and controlled reaction space for biomolecules by combining physical chemistry, nanoscience and enzyme biochemistry. In a biomimetic approach inspired by natural organelles in living cells, we will encapsulate/insert biomolecules (proteins, enzymes) in synthetic nanocompartments to create catalytic reaction spaces with different topology and functionality. We will produce catalytic nanocompartments with "triggered activity" so that in situ reactions inside compartments are activated by opening "protein gates" inserted inside the membrane. A complementary objective is based on producing catalytic nanocompartments acting "in tandem" to support cascade reactions involving a combination of different nanocompartments. Catalytic nanocompartments, producing desired molecules "on demand" serve as simple mimics of natural organelles, whereas those acting "in tandem" mimic chemical communication between organelles. The development of enzymatic reactions in the confined spaces of supramolecular assemblies with nanometer sizes represents a response to the increasing evidence of low bioavailability and stability of directly administrated biopharmaceuticals, and the necessity to produce/detect compounds by controlled cascade reactions between different spatial assemblies in new materials with complex functionality (electronics, medicine, catalysis, food science). The understanding at the molecular level of the relationships between the factors that support successful reactions in confined spaces with different topologies represents a major benefit of this project, which aims to combine model enzymatic reactions with complementary properties resulting from different architectures of the reaction spaces (single-, and in tandem- nanocompartments) Systematic variation of the nanocompartment properties (size, thickness of the membrane, concentration of compartments), and characteristics of the biomolecules (concentration, modification with specific molecular entities, ratio between different biomolecules) will produce efficient interfacing and result in new functional hybrid assemblies. The project combines a fundamental study of the structural changes and interactions that occur when a functional bio-hybrid assembly is generated with applied investigations of the relevant factors and conditions that characterise "model" enzymatic reactions for extension to other reactions necessary for translational applications. This will support the development of a rational design for an efficient platform of catalytic nanocompartments by optimizing the structural and functional details for each type of reaction space (single-, and in tandem- nanocompartments), and straightforward changes of biomolecule or the overall polymer assembly.

Gene therapy constitutes a promising novel modality for treatment of genetic diseases as well as cancer. However, widespread clinical adoption of gene therapies is still in its infancy not least due to various issues associated with using viral vectors to deliver transgenes to target tissues or tumors in patients. Therefore, non-viral delivery methods for DNA and possibly RNA could have advantages in terms of immunogenicity, toxicity, and more. The aim of this project is to develop the next generation of non-viral DNA delivery tools using smart peptide nanoparticles specifically designed to carry theranostic agents comprising DNA and fluorescent molecules (as reporters), and to test them both in vitro and in vivo. We plan to implement extended nucleotide condensing sites of oligo histidines, and decrease the size of the self-assembled system below 50 nm. Our study will provide a two-pronged strategy combining cutting-edge design of nanoscience based carriers with a suite of methods and assays that enable their detailed interrogation and understanding of their delivery mechanisms in vitro and in vivo. It will also form a basis for novel and expanded theranostic strategies due to co-entrapment of fluorescent molecules with large DNA payloads. This capability will, on one hand, enable the delivery of theranostic gene circuits; on the other hand, the entrapment of fluorescent dyes will enable facile readout of particle delivery in time and space that does not rely on gene expression. Importantly, this study takes advantage of established expertise and experimental capabilities in both collaborating labs.