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Despite a growing understanding of factors that drive monomer self-assembly to form supramolecular polymers, the effects of aromaticity gain have been largely ignored. Herein, we document the aromaticity gain in two different self-assembly modes of squaramide-based bolaamphiphiles. Importantly, O → S substitution in squaramide synthons resulted in supramolecular polymers with increased fiber flexibility and lower degrees of polymerization. Computations and spectroscopic experiments suggest that the oxo- and thiosquaramide bolaamphiphiles self-assemble into "head-to-tail"versus "stacked"arrangements, respectively. Computed energetic and magnetic criteria of aromaticity reveal that both modes of self-assembly increase the aromatic character of the squaramide synthons, giving rise to stronger intermolecular interactions in the resultant supramolecular polymer structures. These examples suggest that both hydrogen-bonding and stacking interactions can result in increased aromaticity upon self-assembly, highlighting its relevance in monomer design.

Supramolecular polymers are attractive scaffolds for use as nanocarriers in drug delivery thanks to their modularity and easy fabrication; however, a molecular view into their in vivo behavior is lacking. Herein, we prepare fluorescent squaramide-based supramolecular polymer nanoparticles that range from fibers to spheres while maintaining their surface chemistry and near-neutral surface charge by a co-assembly approach involving a sulfo-cyanine-labeled monomer to track their in vivo biodistribution behavior and clearance in optically transparent zebrafish embryos. Evasion of macrophages, localization of the fibrillar aggregates in the caudal vein, and association with scavenger endothelial cells are observed. The interaction of the fibrillar supramolecular nanoparticles with the caudal vein is abrogated in gene-edited zebrafish lacking Stabilin-2, a receptor analogously found in the mammalian liver, providing a molecular view into their interaction with scavenger endothelial cells. We further show that this interaction can be tuned based on the choice of monomer and its resultant self-assembly.