Natural Cytoskeleton and Programmable Filaments: Bridging Biology, Synthetic Design, and Artificial Cellular Systems

Protein filaments, comprising microtubules, actin, and intermediate filaments, form the eukaryotic cytoskeleton through dynamic self-assembly governed by noncovalent interactions. These structures orchestrate cellular mechanics, architecture, and critical functions, including motility, division, and transport, through precise spatiotemporal regulation of their polymerization cycles. Recent advances in synthetic biology have established synthetic cytoskeletal systems using programmable building blocks that recapitulate or extend native filament functionalities, including controllable assembly and disassembly, directional cargo transport, and mechanochemical signal transduction. This review examines the evolutionary parallels and design divergences between natural and synthetic filaments, emphasizing how biological self-assembly principles can guide the engineering of programmable architectures. Comparative analysis identifies four interconnected design principles for next-generation synthetic filaments: tunable mechanical properties, reversible and energy-coupled nonequilibrium assembly, efficient directional transport or force generation, and feedback-controlled coupling between chemical signals and supramolecular organization. Despite substantial progress, synthetic systems still lag behind natural cytoskeletons in integrating these properties within a single autonomous platform. Bridging this gap will require the convergence of biophysics, synthetic biology, AI-guided molecular design, and automated Design–Build–Test–Learn workflows to connect molecular-scale engineering with adaptive cellular-scale function.