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The constant threat of antimicrobial resistance encouraged in recent years the development of novel antimicrobial strategies. Antimicrobial peptides (AMPs) are highly versatile biomolecules able to disrupt bacterial activity in a plethora of different ways, among which the perturbation and poration of the bacterial membrane. Several effective synthetic AMPs have already been developed and by the use of protein engineering one can design AMPs that self-assemble in nanocapsules for enhanced activity and for drug delivery purposes.
Generalisation of these design strategies must proceed from an accurate knowledge of their interactions with the membrane at the molecular level. In silico techniques such as Molecular Dynamics (MD) simulations can help in extracting molecular mechanisms that are difficult to assess by experiments.
We designed a number of virus-like inspired nanoparticles that show high structural accuracy and dynamic stability in silico, and structural versatility with potential to be functionalised with antimicrobial peptides. We believe that such antibacterial virus-like particles will pave the way to the design of high order delivery systems from simple building blocks with multiple therapeutic capabilities.
Cells in our body and in other organisms are constantly exposed to mechanical signals from their environment. The cell plasma membrane and its underlying actin cytoskeleton are the primary receiver of these signals and act as a processing platform for signalling as well as the uptake and release of cargo, to name a few processes. My research interest lies in the understanding of the molecular and physical principles that govern these processes at the plasma membrane. Particularly, by which mechanisms the force generating machinery of the cell cortex, structural filaments, and motor proteins, govern and regulate the mechanical properties of the cell membrane and dynamics of cell membrane components, and vice versa, how membrane organisation and signalling events feed-back to the regulation of the cortex machinery. These mechanisms, which in turn regulate cell motility and cell-cell interactions, underlie important, poorly understood human diseases that constitute global health problems.
Here, we use reconstituted minimal systems of the membrane – cortex interface to dissect and understand the interlinked contributions of cytoskeletal activity and membrane organisation. We use quantitative imaging approaches, controlled mechanical and biochemical manipulations and work with theoretical physicists to unravel the unsolved puzzle of mechano-sensing and cell membrane tension regulation.
RNA is a central regulator of gene expression. The lack of intrinsically fluorescent natural RNAs has hampered progress considerably. Tools are urgently needed to visualize specific RNAs inside living cells and to observe their processing, interaction, localization, and degradation. In recent years aptamer – fluorogen pairs have gained importance.
Our lab has contributed several aptameric systems for live-cell RNA imaging. Recent work includes SiRA, the first silicon-rhodamine-binding aptamer for super-resolution STED imaging, and RhoBAST, a rhodamine-binding aptamer for super-resolution SMLM RNA imaging. Furthermore, we developed avidity-based aptamers for single-mRNA tracking, and bispecific aptamers for imaging proteins in live and fixed cells.
This lecture will cover the development, features, and applications of the different aptamer-based imaging approaches.
Dynamics are fundamental to the functions of biomolecules and can occur on a wide range of time and length scales. Many bulk techniques average out important events such as transient states, real-time dynamics, and heterogeneity. Here, I will present new high-speed atomic force microscopy (AFM) methods that push the temporal and spatial resolution achievable by any technique for studying single molecules. Additionally, I will introduce NanoLocz, a versatile AFM and high-speed AFM analysis platform that facilitates a variety of high-throughput AFM analysis workflows through a user-friendly interactive interface.
The base composition encoded in nucleic acids provides substantial structures and functional information in the biopolymer. These features of nucleic acids provide the guiding principles for the development of the areas of DNA Nanotechnology and Systems Chemistry.
The lecture will introduce selected examples describing basic concepts and principles to use nucleic acids as functional materials, to engineer biomimetic dynamic circuits, and to harness the frameworks for practical applications. Specifically, the hierarchical stepwise assembly of simple circuits to dynamic networks of enhanced complexities will be described, and subsequently applied for modulating biological transformations in cells and synthetic protocell systems. Specific topics that will be described include: (i) The development of reconfigurable constitutional dynamic networks and transient, dissipative, reaction modules guiding biocatalytic cascades. (ii) The development of spatially localized emergent constitutional dynamic networks driven by enzyme-free catalytic DNA circuits and their application for intracellular imaging of miRNAs. (iii) The development of spatially localized miRNA-driven evolution of constitutional dynamic networks for spatiotemporal gene therapy.
In addition, the dynamic reconfiguration of nucleic acid structures is applied to develop stimuli-responsive carriers for nanomedicine. This will be exemplified with the engineering of nucleic-acid-modified metal-organic framework nanoparticles or hydrogel microcapsules, as stimuli-responsive drug carriers for chemodynamic/photodynamic treatment of cancer cells. Recent advances in the application of phase-separated DNA-based microdroplets as potential temporal drug-release containments and protocell assemblies will be addressed.
Moreover, the triggered reconfiguration of nucleic acid structures introduces versatile means to probe spatiotemporal intracellular transformations by nanotools and nanomachineries. This will be exemplified with: (i) The nucleic acid structures, for the electrochemical detection of cytochrome c in different cellular compartments. (ii) The integration of a photo-triggered CRISPR/Cas12 machinery in cells and the probing of miRNA at cell-cycle phases at the single cell levels.
Boundaries and barriers are part of everyday life. In the molecular world, boundaries composed of lipid bilayers separate compartments but require nanoscale openings to enable crossing of cargo and information. My talk will describe membrane crossing made from the powerful building material of DNA. The synthetic nanostructures mimic natural membrane pores1 but go beyond the scope of biology in terms of large size and defined shape2 as well as controlled nanomechanical movement to regulate transport across the membrane barriers3. Design and creation of the synthetic DNA nanopores follows newly established protocols4 to yield unique nanoarchitectures with well understood self-assembly5, structural dynamics6, membrane interactions7, and cargo transport8. As real-world application, the DNA nanopores can be custom-engineering for portable sensing of diagnostic proteins using commercial handheld devices2. The interdisciplinary work on DNA nanopores impacts on the wider fields of bioengineering9 and materials science10, and -unexpectedly yet pleasingly- graduate teaching11 and research management12.
References: (1) Nat. Nanotechnol. 2017, 12, 619; (2) Nat. Nanotechnol. 2022, 17, 708; (3) Nat. Nanotechnol. 2016, 11, 152; (4) Nat. Protoc. 2021, 16, 86; (5) Nat. Commun. 2022, 13, 3610; (6) Nat. Commun. 2017, 8, 14784. Nat. Commun. 2023, 14, 3630; (7) Nat. Commun. 2018, 9, 1521; (8) Nat. Commun. 2019, 10, 1; (9) Nat. Rev. Chem. 2018, 2, 113; (10) Chem. Soc. Rev. 2023, 52, 1983; (11) Nat. Nanotechnol. 2015, 10, 992; (12) Nat. Rev. Chem. 2022, 6, 81;