Nanofibrillar forms of proteins were initially recognized in the context of pathology, but more recently have been discovered in a range of functional roles in nature, including as active catalytic scaffolds and bacterial coatings. Here we show that protein nanofibrils can be used to form the basis of monodisperse microgels and gel shells composed of naturally occurring proteins. We explore the potential of these protein microgels to act as drug carrier agents, and demonstrate the controlled release of four different encapsulated drug-like small molecules, as well as the component proteins themselves. Furthermore, we show that protein nanofibril self-assembly can continue after the initial formation of the microgel particles, and that this process results in active materials with network densities that can be modulated in situ. We demonstrate that these materials are nontoxic to human cells and that they can be used to enhance the efficacy of antibiotics relative to delivery in homogeneous solution. Because of the biocompatibility and biodegradability of natural proteins used in the fabrication of the microgels, as well as their ability to control the release of small molecules and biopolymers, protein nanofibril microgels represent a promising class of functional artificial multiscale materials generated from natural building blocks.

Naturally spun silks generate fibres with unique properties, including strength, elasticity and biocompatibility. Here we describe a microfluidics-based strategy to spin liquid native silk, obtained directly from the silk gland of Bombyx mori silkworms, into micron-scale capsules with controllable geometry and variable levels of intermolecular β-sheet content in their protein shells. We demonstrate that such micrococoons can store internally the otherwise highly unstable liquid native silk for several months and without apparent effect on its functionality. We further demonstrate that these native silk micrococoons enable the effective encapsulation, storage and release of other aggregation-prone proteins, such as functional antibodies. These results show that native silk micrococoons are capable of preserving the full activity of sensitive cargo proteins that can aggregate and lose function under conditions of bulk storage, and thus represent an attractive class of materials for the storage and release of active biomolecules.

All-aqueous emulsions exploit spontaneous liquid–liquid separation and due to their water-based nature are particular advantageous for the biocompatible storage and processing of biomacromolecules. However, the ultralow interfacial tensions characteristic of all-aqueous interfaces represent an inherent limitation to the use of thermally adsorbed particles to achieve emulsion stability. Here, we use protein nanofibrils to generate colloidosome-like two-dimensional crosslinked networks of nanostructures templated by all-aqueous emulsions, which we term fibrillosomes. We show that this approach not only allows us to operate below the thermal limit at ultra-low surface tensions but also yields structures that are stable even in the complete absence of an interface. Moreover, we show that the growth and multilayer deposition of fibrils allows us to control the thickness of the capsule shells. These results open up the possibility of stabilizing aqueous two-phase systems using natural proteins, and creating self-standing protein capsules without the requirement for three-phase emulsions or water/oil interfaces.

Micro- and nano-scale systems have emerged as important tools for developing clinically useful drug delivery systems. In this tutorial review, we discuss the exploitation of biomacromolecules for this purpose, focusing on proteins, polypeptides, nucleic acids and polysaccharides and mixtures thereof as potential building blocks for novel drug delivery systems. We focus on the mechanisms of formation of micro- and nano-scale protein-based capsules and shells, as well as on the functionalization of such structures for use in targeted delivery of bioactive materials. We summarise existing methods for protein-based capsule synthesis and functionalization and highlight future challenges and opportunities for delivery strategies based on biomacromolecules.