Synthetic cellularity based on non-lipid micro-compartments and protocell models

• Alternative models of protocell micro-compartmentalization based on non-lipid building blocks are reviewed.
• Inorganic protocells are prepared by interfacial assembly of silica nanoparticles.
• Block copolymer and protein–polymer building blocks are exploited for the preparation of enzymatically active protocells.
• Membrane-free protocells with a range of functional properties are prepared by coacervation in aqueous solution.
• Hybrid protocells are produced by self-assembly of fatty acids on the surface of coacervate droplets.

This review discusses recent advances in the design and construction of protocell models based on the self-assembly or microphase separation of non-lipid building blocks. We focus on strategies involving partially hydrophobic inorganic nanoparticles (colloidosomes), protein–polymer globular nano-conjugates (proteinosomes), amphiphilic block copolymers (polymersomes), and stoichiometric mixtures of oppositely charged biomolecules and polyelectrolytes (coacervates). Developments in the engineering of membrane functionality to produce synthetic protocells with gated responses and control over multi-step reactions are described. New routes to protocells comprising molecularly crowded, cytoskeletal-like hydrogel interiors, as well as to the construction of hybrid protocell models are also highlighted. Together, these strategies enable a wide range of biomolecular and synthetic components to be encapsulated, regulated and processed within the micro-compartmentalized volume, and suggest that the development of non-lipid micro-ensembles offers an approach that is complementary to protocell models based on phospholipid or fatty acid vesicles.