Harnessing the Electron-Withdrawing Inductive Effect of One-Component Ionizable Amphiphilic Janus Dendrimers Unveils Cation-π Interactions and Their Important Roles to Targeted mRNA Delivery.

It is expected that current medicine will be complemented or even replaced with genetic nanomedicine, which relies on the targeted delivery of nucleic acids. Delivery of mRNA is accomplished using viral and synthetic four-component vectors which deliver the nucleic acid predominantly to the liver. Our laboratories elaborated a one-component ionizable amphiphilic Janus dendrimer (IAJD) which targets the delivery of mRNA and, therefore, is complementary to viral and synthetic vectors.

Targeted delivery of TGF-β mRNA to murine lung parenchyma using one-component ionizable amphiphilic Janus Dendrimers.

Current clinical strategies for the delivery of pulmonary therapeutics to the lung are primarily targeted to the upper portions of the airways, such as treatment with nebulized instillation and inhalation. However, targeted delivery to the lower regions of the lung is necessary for the treatment of parenchymal lung injury and disease. Here, we show the development of an mRNA therapeutic for the lower lung in mice using one-component Ionizable Amphiphilic Janus Dendrimers as a delivery vehicle.

Toward a Complete Elucidation of the Primary Structure-Activity in Pentaerythritol-Based One-Component Ionizable Amphiphilic Janus Dendrimers for In Vivo Delivery of Luc-mRNA.

Four-component lipid nanoparticles (LNPs) and viral vectors are key for mRNA vaccine and therapeutics delivery. LNPs contain ionizable lipids, phospholipids, cholesterol, and polyethylene glycol (PEG)-conjugated lipids and deliver mRNA for COVID-19 vaccines to liver when injected intravenously or intramuscularly. In 2021, we elaborated one-component ionizable amphiphilic Janus dendrimers (IAJDs) accessing targeted delivery of mRNA.

Unwinding Spherical Helices Increases Entropy and Stability of Frank-Kasper and Body-Centered-Cubic Periodic Arrays To Facilitate Discrimination between Self-Organization Mechanisms.

Spherical supramolecular dendrimers including helical, self-organize soft Frank-Kasper, other cubic such as body-centered cubic, and quasicrystal periodic and quasiperiodic arrays. When any of these periodic or quasiperiodic arrays forms immediately above a columnar phase, a supramolecular orientational memory effect was found to discriminate between mechanisms of self-organization of supramolecular spheres and generate unprecedented periodic arrays of helical columns which cannot be constructed by any other methodology. Here, we demonstrate that unwinding spherical helices, via their precursor nonhelical columns, increases the entropy and stability of their periodic and quasiperiodic spherical arrays and places the Frank-Kasper and other cubic phases immediately above the columnar phase.

Porous helical supramolecular columns self-organized the fluorophobic effect of a semifluorinated tapered dendron.

The self-organizable dendron (4-3,4-3,5)12G2X with X = -CO2CH3 and -CH2OH, an already classic dendron, facilitating the formation of a large diversity of columnar hexagonal phases including crystalline, with intracolumnar order, and liquid crystalline, and providing access for the first time to mimics of the transmembrane protein water channel Aquaporin was semifluorinated at eight of the sp hybridized carbons of its alkyl groups to provide (4-3,4-3,5)4F8G2X. The self-organization of (4-3,4-3,5)4F8G2X was analyzed by a combination of oriented fiber intermediate angle X-ray scattering, wide angle X-ray scattering, electron density maps, and reconstructed X-ray diffractograms by emplying molecular models. These experiments demonstrated that fluorophobic effect of (4-3,4-3,5)4F8G2X mediated mostly the helical confiormation of the fluorinated fragments sharper miocrosegregation of the fluorinated fragments in the most ordered states of the resulting 12 helical porous columns.

Accelerated Ten-Gram-Scale Synthesis of One-Component Multifunctional Sequence-Defined Ionizable Amphiphilic Janus Dendrimer 97.

One-component multifunctional sequence-defined ionizable amphiphilic Janus dendrimers (IAJDs) were discovered in our laboratories in 2021 to represent a new class of synthetic vectors for the targeted delivery of messenger RNA (mRNA). They coassemble with mRNA by simple injection of their ethanol solution into a pH 4 acetate buffer containing the nucleic acid into monodisperse dendrimersome nanoparticles (DNPs) with predictable dimensions. DNPs are competitive with 4-component lipid nanoparticles (LNPs), which are used in commercial COVID-19 vaccines, except that IAJDs are prepared in fewer reaction steps than each individual component of the LNPs.

Hierarchical Self-Organization and Disorganization of Helical Supramolecular Columns Mediated by H-Bonding and Shape Complementarity.

H-bonding, shape complementarity, and quasi-equivalence are widely accepted as some of the most influential molecular recognition events mediating biological and synthetic self-organizations. H-bonds are weaker than ionic but stronger than van der Waals forces. However, the directionality of H-bonds makes them the most powerful among all nonbonding interactions.

Designing Highly Ordered Helical and Nonhelical Porous Crystalline and Disordered Nonhelical Columnar Liquid Crystalline Self-Organizations.

Helical self-organizations are equilibrium structures responsible for the assembly of nonequilibrium and equilibrium living and synthetic systems. Racemic helical columnar systems transform into one-handed systems with the help of enantiomerically rich or pure components. Racemic, enantiomerically rich, and enantiomerically pure helical periodic arrays of columns are analyzed by oriented fiber X-ray diffraction (XRD).

Targeted delivery of TGF-β mRNA to lung parenchyma using one-component ionizable amphiphilic Janus Dendrimers.

Current clinical strategies for the delivery of pulmonary therapeutics to the lung are primarily targeted to the upper portions of the airways. However, targeted delivery to the lower regions of the lung is necessary for the treatment of parenchymal lung injury and disease. Here, we have developed an mRNA therapeutic for the lower lung using one-component Ionizable Amphiphilic Janus Dendrimers (IAJDs) as a delivery vehicle.

Cogwheel Mechanism of Helical Self-Organization is Thermodynamically Controlled, Self-Repairing, and Universal.

The cogwheel mechanism of helical self-organization, reported by us, generates columns with the alkyl chains of their components parallel to the column axis. This mechanism disregards the enantiomeric purity of constituents and, under suitable design, provides the fastest rate of helical self-organization. Here, we investigate the supramolecular structure of a thermodynamically controlled helical self-organization system.

Aptamer-Targeted Dendrimersomes Assembled from Azido-Modified Janus Dendrimers "Clicked" to DNA.

Amphiphilic Janus dendrimers (JDs), synthetic alternatives to lipids, have the potential to expand the scope of nanocarrier delivery systems. JDs self-assemble into vesicles called dendrimersomes, encapsulate both hydrophobic cargo and nucleic acids, and demonstrate enhanced stability in comparison to lipid nanoparticles (LNPs). Here, we report the ability to enhance the cellular uptake of Janus dendrimersomes using DNA aptamers.

The Constitutional Isomerism of One-Component Ionizable Amphiphilic Janus Dendrimers Orchestrates the Total and Targeted Activities of mRNA Delivery.

Constitutional isomerism has been previously demonstrated by one of our laboratories to represent a powerful design strategy for the elaboration of complex functional self-organizations. Here we report the design, synthesis, and characterization of 14 positional, skeletal, and functional constitutional isomeric one-component, multifunctional, sequence-defined, amphiphilic ionizable Janus dendrimers (IAJDs). Their coassembly by simple injection with luciferase mRNA (Luc-mRNA) to form dendrimersome nanoparticles (DNPs) was studied.

From Frank-Kasper, Quasicrystals, and Biological Membrane Mimics to Reprogramming the Living Factory to Target the Delivery of mRNA with One-Component Amphiphilic Janus Dendrimers.

This Perspective is dedicated to the 25th Anniversary of . It provides a personal view on the developing field of the polymer and biology interface over the 25 years since the journal was launched by the American Chemical Society (ACS). This Perspective is meant to bridge an article published in the first issue of the journal and recent bioinspired developments in the laboratory of the corresponding author.

Glycan-Driven Formation of Raft-Like Domains with Hierarchical Periodic Nanoarrays on Dendrimersome Synthetic Cells.

The accurate spatial segregation into distinct phases within cell membranes coordinates vital biochemical processes and functionalities in living organisms. One of nature's strategies to localize reactivity is the formation of dynamic raft domains. Most raft models rely on liquid-ordered phases in a liquid-disordered phase lacking correlation and remaining static, often necessitating external agents for phase separation.

Targeted and Equally Distributed Delivery of mRNA to Organs with Pentaerythritol-Based One-Component Ionizable Amphiphilic Janus Dendrimers.

Delivery of nucleic acids with viral and synthetic vectors has pioneered genetic nanomedicine. Four-component lipid nanoparticles (LNPs) consisting of ionizable lipids, phospholipids, cholesterol, and PEG-conjugated lipids, assembled by microfluidic or T-tube, are the benchmark synthetic vector for delivery of mRNA. One-component multifunctional sequence-defined ionizable amphiphilic Janus dendrimer (IAJD) delivery systems for mRNA were developed by us to complement LNPs.

Stimuli-Responsive Principles of Supramolecular Organizations Emerging from Self-Assembling and Self-Organizable Dendrons, Dendrimers, and Dendronized Polymers.

All activities of our daily life, of the nature surrounding us and of the entire society and its complex economic and political systems are affected by stimuli. Therefore, understanding stimuli-responsive principles in nature, biology, society, and in complex synthetic systems is fundamental to natural and life sciences. This invited Perspective attempts to organize, to the best of our knowledge, for the first time the stimuli-responsive principles of supramolecular organizations emerging from self-assembling and self-organizable dendrons, dendrimers, and dendronized polymers.

Assembling Complex Macromolecules and Self-Organizations of Biological Relevance with Cu(I)-Catalyzed Azide-Alkyne, Thio-Bromo, and TERMINI Double "Click" Reactions.

In 2022, the Nobel Prize in Chemistry was awarded to Bertozzi, Meldal, and Sharpless "for the development of click chemistry and biorthogonal chemistry". Since 2001, when the concept of click chemistry was advanced by Sharpless laboratory, synthetic chemists started to envision click reactions as the preferred choice of synthetic methodology employed to create new functions. This brief perspective will summarize research performed in our laboratories with the classic Cu(I)-catalyzed azide-alkyne click (CuAAC) reaction elaborated by Meldal and Sharpless, with the thio-bromo click (TBC) and with the less-used, irreversible TERminator Multifunctional INItiator (TERMINI) dual click (TBC) reactions, the last two elaborated in our laboratory.

Self-Assembly of Glycerol-Amphiphilic Janus Dendrimers Amplifies and Indicates Principles for the Selection of Stereochemistry by Biological Membranes.

The principles for the selection of the stereochemistry of phospholipids of biological membranes remain unclear and continue to be debated. Therefore, any new experiments on this topic may help progress in this field. To address this question, three libraries of constitutional isomeric glycerol-amphiphilic Janus dendrimers (JDs) with nonsymmetric homochiral, racemic, and symmetric achiral branching points were synthesized by an orthogonal-modular-convergent methodology.

Zwitterionic Dendrimersomes: A Closer Xenobiotic Mimic of Cell Membranes.

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 (JD ) and a 3,5-substituted dihydrobenzoate-based hydrophobic dendron is introduced.

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

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.

Targeted Delivery of mRNA with One-Component Ionizable Amphiphilic Janus Dendrimers.

Targeted and efficient delivery of nucleic acids with viral and synthetic vectors is the key step of genetic nanomedicine. The four-component lipid nanoparticle synthetic delivery systems consisting of ionizable lipids, phospholipids, cholesterol, and a PEG-conjugated lipid, assembled by microfluidic or T-tube technology, have been extraordinarily successful for delivery of mRNA to provide Covid-19 vaccines. Recently, we reported a one-component multifunctional sequence-defined ionizable amphiphilic Janus dendrimer (IAJD) synthetic delivery system for mRNA relying on amphiphilic Janus dendrimers and glycodendrimers developed in our laboratory.

An Accelerated Modular-Orthogonal Ni-Catalyzed Methodology to Symmetric and Nonsymmetric Constitutional Isomeric AB to AB Dendrons Exhibiting Unprecedented Self-Organizing Principles.

Five libraries of natural and synthetic phenolic acids containing five AB, ten constitutional isomeric AB, one AB, and one AB were previously synthesized and reported by our laboratory in 5 to 11 steps. They were employed to construct seven libraries of self-assembling dendrons, by divergent generational, deconstruction, and combined approaches, enabling the discovery of a diversity of supramolecular assemblies including Frank-Kasper phases, soft quasicrystals, and complex helical organizations, some undergoing deracemization in the crystal state. However, higher substitution patterns within a single dendron were not accessible.

One-Component Multifunctional Sequence-Defined Ionizable Amphiphilic Janus Dendrimer Delivery Systems for mRNA.

Efficient viral or nonviral delivery of nucleic acids is the key step of genetic nanomedicine. Both viral and synthetic vectors have been successfully employed for genetic delivery with recent examples being DNA, adenoviral, and mRNA-based Covid-19 vaccines. Viral vectors can be target specific and very efficient but can also mediate severe immune response, cell toxicity, and mutations.

Enhanced Concanavalin A Binding to Preorganized Mannose Nanoarrays in Glycodendrimersomes Revealed Multivalent Interactions.

The effect of the two-dimensional glycan display on glycan-lectin recognition remains poorly understood despite the importance of these interactions in a plethora of cellular processes, in (patho)physiology, as well as its potential for advanced therapeutics. Faced with this challenge we utilized glycodendrimersomes, a type of synthetic vesicles whose membrane mimics the surface of a cell and offers a means to probe the carbohydrate biological activity. These single-component vesicles were formed by the self-assembly of sequence-defined mannose-Janus dendrimers, which serve as surrogates for glycolipids.