Self-assembling sugars as synthetic capsids

All living organisms, from the simplest bacteria to complex multicellular life forms, rely on a common set of molecular building blocks: lipids, nucleic acids, proteins, and saccharides, that orchestrate cellular structure, function, and replication. These molecules operate within defined functional boundaries, a principle also mirrored in viral architectures that exploit host biochemistry using the same building blocks. In viruses, proteins and lipids typically package and protect nucleic acids,4,6 a strategy that is emulated in synthetic systems for gene delivery and vaccine design. Synthetic proteins have been designed to mimic viral capsid proteins, successfully encapsulating double-stranded nucleic acid and protecting it from nuclease degradation.8 Smaller oligopeptides also successfully embedded nucleic acid but have yet to demonstrate protective activity.11 While small molecules can form rod-like assemblies with nucleic acids, they do not achieve true capsid-like encapsulation.12-18 Here we show that a specially designed saccharidic molecule, a self-assembling cyclodextrin (CD), can encapsulate oligonucleotides into linear, virus-like fibres with protective functionality.22 The co-assembly we report comprises nanometre-scale tubular fibres of seven CD-based protofibrils that encapsulate oligonucleotides. A cryo-EM structure at 3.3 Å resolution unveils the intricate details of this co-assembly at the molecular scale. Molecular dynamics simulations and statistical mechanical calculations reveal that structural adaptability, rather than fully ordered packing, drives the cooperative self-assembly with entropy playing a pivotal role in stabilizing the fibre architecture. Unlike conventional capsids that rely on uniformity and tight packing, our system benefits from disorder arising via gaps in oligonucleotide packing as well as bending fluctuations that promote stable encapsulation. This study introduces a novel paradigm in molecular design, where sugars replace proteins and entropic contributions enhance, rather than disrupt, multi-component self-assembly. These results broaden the functional repertoire of saccharides in molecular engineering and open new avenues for non-viral gene delivery systems, potentially leading to better customizable and biocompatible therapeutic platforms.