Recent advances in materials science and nanoscale fabrication techniques enable bio-inspired materials systems that simulate biological remarkable functions. Technology to control the nanostructure of self-organized materials is indispensable in the development of advanced biomaterials. Prof. Kazunari Akiyoshi proposed a new strategy for preparation of bio-inspired functional nanoparticles and their bottom-up design of biomaterials based on the concept of self-organization of biocomponents such as lipids, proteins, nucleic acids, and polysaccharides. Through use of such new biomaterials, he developed new cancer therapies, vaccines and tissue engineering platforms, from fundamental studies through to practical applications for advanced biomedical technologies. His major achievements are summarized below.

1. Development of nanogel engineering
Prof. Akiyoshi developed new method for preparation of physically cross-linked nanometer sized hydrogel nanoparticle (self-Nanogel) with three-dimensional networks by controlled association of hydrophobically modified polymers (associating polymer) in water. For example, cholesteryl group-modified pullulan (CHP) that pullulan is partially substituted with cholesterol moieties forms stable mono-dispersive nanogels with hydrophobic cross-linking domains and a diameter of about -30 nm. Naturally occurring polysaccharides as a backbone polymer are useful for biomedical application because of their excellent biocompatibility and availability. The self-Nanogel formed hybrid complexes with proteins or nucleic acids, and also formed nanogel-inorganic (apatite or silica) hybrids. Various stimuli-responsive nanogels with pH, temperature and light were constructed by self-assembly of functional associating polymers.
Conventional hydrogels have been widely used as functional materials in biotechnological and biomedical applications. However, designing hydrogels with a well-controlled nanodomain structure remains challenging. Prof. Akiyoshi proposed nanogel tectonic engineering for biomedical application. This involves design of mainly polysaccharide self-Nanogel tectons (building units) and the construction of functional hierarchical gels or interfaces through their bottom-up assembly. For example, polysaccharide nanogels cross-linked (NanoClik) microsphere, porous gels, fiber and sheet have been designed. Nanogel tectonic engineering provides a new paradigm for development of new gel biomaterials with well-organized three-dimensional structures, multiple functions, sensitivity to a range of different stimuli, and programmed responses that can be controlled temporally and spatially.

2. Development of molecular chaperon-inspired system for bioapplication
In living systems, molecular chaperones selectively trap heat-denatured proteins or their intermediates, primarily by hydrophobic interactions, to prevent irreversible aggregation owing to macromolecular host (molecular chaperone)- guest (protein) interactions. Prof. Akiyoshi developed that amphiphilic self-Nanogels act as artificial molecular chaperones in which nanogels trap denatured proteins and assist protein refolding. The colloidal and thermal stability of proteins significantly increased by complexation with nanogels. Nowadays, protein therapeutics has become important for treating a variety of diseases. However, effective delivery of proteins remains a challenge due to instability and short half-lives. The molecular chaperon engineering is a new concept that has led to breakthroughs in development of new protein delivery system for nanomedicine and tissue engineering. In fact, self-Nanogel of amphiphilic polysaccharides acted as an effective protein-based antigen delivery nanocarrier for efficient cancer vaccine system and also for intranasal vaccine system. The nanogel-tectonic materials with chaperon function were useful as new functional scaffolds in tissue engineering.

3. Development of biomembrane-inspired system
Membrane proteins play central roles in various superior functions of biological membranes and are attracting attention as bio-nanodevices. However, membrane proteins are difficult to isolate and purify as functional forms due to the high hydrophobicity. Prof. Akiyoshi proposed a chaperoning system using liposome in cell-free membrane protein synthesis. He found that various expressed membrane proteins, such as apo-cytochrome b5, connexin 43, bacteriorhodopsin, KcsA channel membrane protein and aggregation-prone membrane proteins from Escherichia coli were incorporated directly into liposomes and efficiently formed proteoliposomes. By using this proteoliposome engineering, he demonstrated that new drug delivery system comprising connexin 43-integrated liposomes had the potential to transfer small molecules into the cytoplasm directly. Functional proteoliposomes would enable innovative breakthroughs in nanocarrier technologies for use in drug delivery system and also in a new platform for membrane protein chips in bioanalysis.

As mentioned above, Prof. Akiyoshi developed many new functional nano biomaterials by controlling the self-assembly of biomolecules and biopolymers, and new concepts of nanogel tectonics engineering, chaperone function engineering, and proteoliposome engineering. He proposed not only basic research for the creation of new nanobiomaterials but also the way to their biomedical applications. Therefore, his achievement was recognized as worthy of the Japan Chemical Society Award.