Showing papers by "Virgil Percec published in 2022"

The Unexpected Importance of the Primary Structure of the Hydrophobic Part of One-Component Ionizable Amphiphilic Janus Dendrimers in Targeted mRNA Delivery Activity.

Abstract: Viral and synthetic vectors for delivery of nucleic acids impacted genetic nanomedicine by aiding the rapid development of the extraordinarily efficient Covid-19 vaccines. Access to targeted delivery of nucleic acids is expected to expand the field of nanomedicine beyond most expectations. Both viral and synthetic vectors have advantages and disadvantages. The major advantage of the synthetic vectors is their unlimited synthetic capability. The four-component lipid nanoparticles (LNPs) are the leading nonviral vector for mRNA used by Pfizer and Moderna in Covid-19 vaccines. Their synthetic capacity inspired us to develop a one-component multifunctional sequence-defined ionizable amphiphilic Janus dendrimer (IAJD) delivery system for mRNA. The first experiments on IAJDs provided, through a rational-library design combined with orthogonal-modular accelerated synthesis and sequence control in their hydrophilic part, some of the most active synthetic vectors for the delivery of mRNA to lung. The second experiments employed a similar strategy, generating, by a less complex hydrophilic structure, a library of IAJDs targeting spleen, liver, and lung. Here, we report preliminary studies designing the hydrophobic region of IAJDs by using dissimilar alkyl lengths and demonstrate the unexpectedly important role of the primary structure of the hydrophobic part of IAJDs by increasing up to 90.2-fold the activity of targeted delivery of mRNA to spleen, lymph nodes, liver, and lung. The principles of the design strategy reported here and in previous publications indicate that IAJDs could have a profound impact on the future of genetic nanomedicine.

Self-organization of rectangular bipyramidal helical columns by supramolecular orientational memory epitaxially nucleated from a Frank-Kasper σ phase

Abstract: Programming living and soft complex matter via primary structure and self-organization represents the key methodology employed to design functions in biological and synthetic nanoscience. Memory effects have been used to create commercial technologies including liquid crystal displays and biomedical applications based on shape memory polymers. Supramolecular orientational memory (SOM), induced by an epitaxial nucleation mediated by the close contact spheres of cubic phases, emerged as a pathway to engineer complex nanoscale soft matter of helical columnar hexagonal arrays. SOM preserves the crystallographic directions of close contact supramolecular spheres from the 3D phase upon cooling to the columnar hexagonal periodic array. Despite the diversity of 3D periodic and quasiperiodic nanoarrays of supramolecular dendrimers, including Frank-Kasper and quasicrystal, all examples of SOM to date were mediated by Im3¯m (body-centered cubic, BCC) and Pm3¯n (Frank-Kasper A15) cubic phases. Expanding the scope of SOM to non-cubic arrays is expected to generate additional morphologies that were not yet available by any other methods. Here we demonstrate the SOM of a dendronized triphenylene that self-organizes into helical columnar hexagonal and tetragonal P4/mnm (Frank-Kasper σ) phases. Structural analysis of oriented fibers by X-ray diffraction reveals that helical columnar hexagonal domains self-organize an unusual rectangular bipyramidal morphology upon cooling from the σ phase. The discovery of SOM in a non-cubic Frank-Kasper phase indicates that this methodology may be expanded to other periodic and quasiperiodic nanoarrays organized from self-assembling dendrimers and, most probably, to other soft and living complex matter.

Zwitterionic Dendrimersomes: A Closer Xenobiotic Mimic of Cell Membranes

Abstract: Building functional mimics of cell membranes is an important task toward the development of synthetic cells. So far, lipid and amphiphilic block copolymers are the most widely used amphiphiles with the bilayers by the former lacking stability while membranes by the latter are typically characterized by very slow dynamics. Herein, a new type of Janus dendrimer containing a zwitterionic phosphocholine hydrophilic headgroup (JDPC) and a 3,5‐substituted dihydrobenzoate‐based hydrophobic dendron is introduced. JDPC self‐assembles in water into zwitterionic dendrimersomes (z‐DSs) that faithfully recapitulate the cell membrane in thickness, flexibility, and fluidity, while being resilient to harsh conditions and displaying faster pore closing dynamics in the event of membrane rupture. This enables the fabrication of hybrid DSs with components of natural membranes, including pore‐forming peptides, structure‐directing lipids, and glycans to create raft‐like domains or onion vesicles. Moreover, z‐DSs can be used to create active synthetic cells with life‐like features that mimic vesicle fusion and motility as well as environmental sensing. Despite their fully synthetic nature, z‐DSs are minimal cell mimics that can integrate and interact with living matter with the programmability to imitate life‐like features and beyond.

Shape Control over the Polymer Molecular Weight Distribution and Influence on Rheological Properties

Abstract: The shape, breadth, and average molecular weight of the overall molecular weight distribution (MWD) largely define polymer properties. In conventional free-radical polymerization, control over this distribution is through the many competing kinetic pathways dominated by radical termination events. “Living” radical polymerization mechanistically minimizes these termination events, providing a facile route to a desired Gaussian distribution with the distribution breadth dependent upon the activity of the catalyst or modulating agent. However, producing unusually shaped distributions can only be achieved through modeling of the complex polymerization kinetics and invoking feeding and other methods. Here, we construct square, slanted, and chair-like MWDs by blending two to four polymers made using a low-reactive RAFT agent with dispersities close to 2. The synthesis of these polymers, unlike that of polymers made with high-reactive RAFT agents, is simple, scalable, and importantly reproducible as the MWD is independent of conversion, making this polymerization method virtually and kinetically model-free. The blending method described here overcomes many of the difficulties in producing unusually shaped MWDs and allows control over the shape and breadth of the MWD. The concept further provides a general synthetic strategy for studying important structure–property relationships of polymers with desired processing and performance characteristics. This is demonstrated by measurement and modeling analysis of the linear viscoelastic properties of selected samples, which provides a way to tailor the properties of polymers by controlling the form of their MWD via blending. Unlike conventional approaches analyzing the effects of the MWD, its actual shape is considered and its effect on the properties is addressed.

Molecular Design Principles to Target mRNA Delivery With One-Component Ionizable Amphiphilic Janus Dendrimers Derived From Plant Phenolic Acids

Abstract: Viral and synthetic vectors for the delivery of nucleic acids were key to the rapid development of the extraordinarily efficient Covid-19 vaccines and of genetic nanomedicine. The four-component lipid nanoparticles, statistically distributed in nanoparticles, are the leading delivery non-viral vector used by BioNTech/Pfizer and Moderna to access their Covid-19 mRNA vaccines. Here we report the molecular design principles to target mRNA delivery and activity with a one-component ionizable multifunctional amphiphilic Janus dendrimer system derived from plant phenolic acids. The precise location of the functional groups in the one-component system demonstrates target being induced by the hydrophilic region and activity by the hydrophobic domain of the Janus. These principles, and a hypothetic mechanism explaining them, simplify preparation, handling and storage of vaccines, reduce price, while employing renewable starting materials. Therefore, an increased accessibility to a large diversity of mRNA-based vaccines and nanotherapeutics may become available by simple molecular design principles.