Dipankar Sahoo

Genetic nanomedicine delivers nucleic acids by viral and synthetic vectors to produce drugs directly in the body’s own cells. Each approach presents relative advantages, but synthetic vectors are distinguished by their effectively unlimited synthetic capabilities. The leading synthetic vectors are the four-component lipid nanoparticles (LNPs) used in the Pfizer and Moderna Covid-19 vaccines, which deliver mRNA to the liver. Inspired by this concept, our laboratories developed a one-component, multifunctional, sequence-defined ionizable amphiphilic Janus dendrimer (IAJD) that delivers mRNA predominantly to the more desirable spleen, as well as to other organs. Benzoyl, benzyl, and aliphatic biodegradable esters connect the hydrophobic and hydrophilic domains of IAJDs. IAJDs have already been used in preclinical studies of therapeutics and vaccines, and several are commercially available. Here we report that, unexpectedly, the least stable benzyl-ester-based IAJDs, which contain the 1-(2-hydroxyethyl)piperazine ionizable amine (IA), undergo an extraordinarily slow, self-catalyzed transesterification at room temperature that transforms the one-component system into a multicomponent one. This reaction progressively extends the hydrophilic ionizable-amine domain from monomer to dimer, trimer, tetramer, and pentamer, generating a mixture of the original IAJD, its oligomers, and the released benzyl alcohol. Remarkably, at up to 50% transesterification, the in vivo activity of this multicomponent system remains similar to that of the parent one-component IAJD. Beyond providing a simple in situ method to convert one-component IAJDs into an unprecedented multicomponent IAJDs system, these results establish a new design strategy to construct the hydrophilic domain of one-component IAJDs through a complex, “vertical”, sequence-defined arrangement of IAs.

This account discusses the accidental discovery of self-assembling and self-organizable dendrons, dendrimers, and dendronized polymers. Our laboratory never intended to make this discovery. At the time of this finding, our laboratory was interested in developing a methodology to mimic the self-assembly of helical rod-like and icosahedral or spherical viruses. An attempt to transform a monotropic biaxial nematic (N _b ) phase of a compound constructed from a combination of a half-disc and a rod into an enantiotropic phase by attaching this building block as a side group to a polymer led to a polymer coated with a helical dendritic jacket appearing as a primitive rod-like virus. Investigation of more and less complex variants of the half-disc and rod compound led to the discovery of self-organizable dendrons, dendrimers, and dendronized polymers assembling into both helical rod-like and spherical helices supramolecular dendrimers. The combination of a disc-like and a rod-like compound that never exhibits the N _b phase was developed in France and published in this journal. Our discovery provided an example in which an incorrect assignment of a phase led to a finding that facilitated the development of several new unrelated research fields, all pioneered by self-assembling and self-organizable dendrons, dendrimers, and dendronized polymers. We would like to use this opportunity to thank the scientists who elucidated the structure and the mechanism of self-assembly of viruses, the laboratory that developed the combination of disc-like and rod-like molecules, and the scientists who asked us to investigate this molecule for providing the inspiration for this discovery.

Our laboratory has reported an unprecedented cogwheel mechanism of helical self-organization, which generates microdomains of single-handed supramolecular columns while disregarding the chirality of its building blocks. Discovered with a dendronized perylene bisimide (PBI), this mechanism arranges the alkyl groups of the self-assembling dendrons parallel to the helical column, providing the most compact helical construct known. Four precise molecular elements were originally considered to be required by the design of this helical structure. The first three elements─alkyl group length, the presence of a chiral methyl group on the alkyl chain, and the parallel arrangement of the helical coat to the column long axis─were demanded by a dimer of the dendronized PBI with 45° internal rotation of PBI units within dimer and a 90° rotation of dimers along the column long axis. Previous experiments demonstrated that a self-repairing process relaxes the number of carbons and eliminates the need for a chiral methyl group within the alkyl chains of the dendronized building block, essential to predict the helical half-pitch and helical coat arrangement. In this work, we demonstrate that the PBI dimer can be replaced by a repeat unit formed from one PBI and three nondendronized aromatic groups. Combined with the previously reported results, this extraordinary tolerance of the cogwheel mechanism to structural defects places it high on the list of models to study the origins of biological homochirality and for numerous practical applications.

Helical homochirality is available in nature, biology, and, most recently, also in synthetic systems. Selected examples of helical complex systems from nature, biology, and synthetic chemistry will be briefly discussed, most probably for the first time, in a single publication. When available, the mechanisms of the origin of their homochirality will be presented. In order to encourage new discoveries, the historical events of many discoveries will also be highlighted. Potential connections between homochirality in nature and biology, as well as in nature- and bio-inspired macroscopic, molecular, and supramolecular complex systems, will be mentioned.

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. Simplified synthesis and assembly processes allow for rapid IAJD screening for discovery. The role of the primary structure of IAJDs in activity indicated, with preliminary investigations, that ionizable amine (IA), sequence, and architecture of hydrophilic and hydrophobic domains are important for in vivo targeted delivery. Here, we study the role of the interconnecting linker length between the IA and the hydrophobic domain of pentaerythritol-based IAJDs. The linker length determines, through inductive effects, the position of the IA and the pK_a of the IAJDs and through flexibility, the stability of the DNPs, highlighting their extraordinarily important role in effective targeted delivery.

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. This process is not available in biology where spherical viruses self-organize body-centered cubic lattices. However, this concept reengineers, on increasing temperature, the originally expected position of the periodic and quasiperiodic array versus that of the columnar lattice. This process facilitates discrimination between different self-organization mechanisms of supramolecular spheres and also mediates the emergence of unprecedentedly complex and technologically important periodic arrays of nonhelical columns.

Living cationic ring‐opening polymerization accompanied by isomerization of cyclic imino ethers is performed at high temperatures that provide access to the synthesis of self‐organizable systems in their isotropic melt or solution state. This Perspective discusses fundamental mechanistic principles of this polymerization and bridges with the polymerization of dendronized cyclic iminoethers forming polymers that self‐organize soft Frank–Kasper and quasicrystal periodic and quasiperiodic arrays. These two fields represent frontiers in macromolecular and supramolecular science. A brief discussion of the impact of this polymerization on biomaterials and how it impacted contemporary mechanistic investigations is also made. Expected impacts via future synthetic developments and mechanistic investigations are discussed.

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 sp³ 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 via the helical confiormation of the fluorinated fragments sharper miocrosegregation of the fluorinated fragments in the most ordered states of the resulting 12₄ helical porous columns. These results support the original model of self-organization of dendrons and provide access to new and simpler synthetic avenues for the construction of mimics of aquaporin channels which are of great interest for cell biology and for the next generation of membranes for water separation and water purification.