Self-assembled structures in Nature play essential roles in living systems, such as, in protein folding and the formation of biological membranes. The formation of most biological nanostructures is driven by self-assembly processes. For example, the self-assembly of phospholipids forms cell membranes, DNA forms a double helix through specific hydrogen bonding of individual strands, and proteins form by the folding of polypeptide chains to make defined tertiary and quaternary structures. Nature has inspired us to make biomimetic self-assembled structures. Furthermore, the assembly and transformation of biomacromolecules in response to a signal (or a stimulus) is an important component to most of Nature’s functions and signaling mechanisms. Given the versatile nature of such stimuli-responsive assembly and disassembly processes, it is desirable to understand and develop ways by which artificial, responsive supramolecular assemblies could be achieved. Development of artificial assemblies with nature’s specificity and versatility stands as an enormous intellectual challenge and custom-designed stimuli-sensitive supramolecular assemblies have potential in a variety of applications.
Nanomedicine for Cancer Therapy
Noncovalent Polymer Gatekeeper in Mesoporous Nanparticles
Non-covalently binding drug molecules and then releasing them in response to an external trigger has been an important goal. Mesoporous silica nanoparticles with gatekeeper strategies could release the drug molecules in response to specific stimuli. However, it requires complex chemical modification of mesoporous silica nanoparticles, hence limiting their capability to encapsulate high amount of drug and versatility for ligand functionalization. We developed a novel polymer gatekeeper that can noncovalently block the pores of mesoporous silica nanoparticles and be simply modified with targeting ligands. Hydrophilic/hydrophobic drug molecules can be encapsulated at high doses, since the mesoporous silica nanoparticles are not chemically modified, thereby providing maximum pore volume. Moreover, noncovalently encapsulated drugs can be released in response to intracellular glutathione concentrations after cellular internalization by receptor-mediated uptake.
Protein Gatekeeper in Mesoporous Nanparticles
Nanomachine for Cell Penetration
Intracellular Bioactive Supramolecular Assembly
The formation of most biological nanostructures is driven by self-assembly processes and the structured biomaterials have biochemical activities such as enzyme activity and protein signaling. The artificial assembly of synthetic building units inside a living cell and the interaction of these units with the cellular components have rarely been studied, but are emerging as an intriguing strategy to control cellular fate. In particular, self-assembly inside cellular organelles is challenging because of the practical difficulty in observing the complex intracellular environment, and thus has not yet been reported. Achievement of artificial self-assembly of small molecules inside such organelles could be an advanced strategy for an efficient external control over organelle function and manipulation of the cellular fate.
Organelle Localization Induced Self assembly of Peptide Amphiphile to Control the Cell fate
Self assembly is a well established phenomenon over decades, however self assembly of building units to form interesting nano structures inside living cells are something amazing and is exciting when they could control the cellular fate like proliferation, apoptosis and metabolism. Self assembly is an equilibrium process between the individual building units and their aggregated state, and the concentration of the molecules should be over the critical value to induce assembly. So it is critical to think about reducing the effective concentration for more practicability. An Organalle Localization Induced Self assembly (OLISA) is more promising and reliable. In here, the building units accumulate inside cellular organelle, thereby increasing the effective concentration (~500-1000) compared with feeding concertation. OLISA is a pioneering approach which open up huge possibility to control the cell fate as well as investigating cellular pathways and functions.
Mitochondria Targeting Drug
Mitochondrial TRAP1 inhibitor
The crystal structures of human TRAP1 complexed with Hsp90 inhibitors conjugated to a mitochondria-targeting moiety was developed, and we investigated the rational development of a mitochondria-targeted Hsp90 inhibitor to specifically inactivate TRAP1. We showed crystal structures of both the open and closed TRAP1 conformations, and can, therefore, suggest molecular mechanisms of conformational change during the TRAP1 ATPase cycle, which will also aid in understanding the general mechanisms of Hsp90 chaperone function. In regard to development of mitochondrial Hsp90 inhibitors as cancer drugs, we clearly demonstrated that TRAP1 predominates over Hsp90 in cancer cell mitochondria and showed limitations of current Hsp90 inhibitors for inactivating the mitochondrial pool of TRAP1, primarily due to inefficient accumulation in mitochondria. Instead of designing specific inhibitors to the TRAP1 ATP pocket, we generated mitochondrial TRAP1-selective inhibitors by modifying current Hsp90 inhibitors to become “mitochondria-specific”. The concept of “organelle-specific” can be broadly applied to increase drug efficacy and minimize side effects for many drugs targeting proteins in mitochondria.
Mitochondrial Targeted Photodynamic Therapy
Supramolecular Assembly for Energy Materials
Multifunctional Molecular Design as an Efficient Polymeric Binder for Silicon Anodes in Lithium-Ion Batteries