The dynamics of molecular assembly and disassembly disrupt cellular structures, affecting biological functions. When a molecule is photoresponsive, its assembly and disassembly can be driven and controlled by light to provoke specific biological responses. A new, photoswitchable molecule, developed at Ulsan National Institute of Science (UNIST), demonstrates repeatable, reversible assembly-disassembly capabilities when it is irradiated with different wavelengths of light. The molecule, named Mito-AZB, is based on synthetic building blocks composed of an azobenzene moiety and an organelle membrane-targeting unit. It is designed to target specific mitochondria within cells with high spatiotemporal precision. Mito-AZB can be used in basic research and in light therapies to inhibit cancerous cell growth in skin cancer, for example. For its development, the researchers integrated the targeting moiety that guides the molecule to mitochondria with an azobenzene unit that undergoes reversible structural changes upon light irradiation, and a fluorescent dye that enables real-time visualization using microscopy. Researchers developed a photoresponsive molecular system capable of repeatedly assembling and disassembling in response to specific wavelengths. When the molecule is localized to an organelle membrane and repeatedly cycled through assembly and disassembly, the membrane becomes damaged, its integrity is disrupted, and apoptosis is induced. Courtesy of S. Kim, D. Kim, Y. Jo, et al, “Photoregulated Assembly-Disassembly Dynamics of Interfering with Organelle Membrane Integrity,” Nano Letters, (2025), and Ulsan National Institute of Science and Technology. When Mito-AZB molecules are localized to an organelle membrane, they self-assemble into supramolecular fibrils that can interact with the membrane in different ways. When the Mito-AZB molecules are exposed to visible light at 450 nm, they assemble into a robust fibrous structure, exerting mechanical stress on the target mitochondrial membrane. When the same molecules are irradiated with ultraviolet (UV) light at 350-365 nm, trans-to-cis isomerization of the azobenzene units is induced, and the fibers disassemble. The transition from fibrillar to amorphous assemblies is associated with a reduction in membrane affinity. The reversible, light-driven assembly-disassembly process gives the researchers dynamic control of the membrane binding strength, ultimately disrupting organelle membrane integrity through cyclic weakening and the strengthening of supramolecular interactions. Experimental results demonstrated that, following localization of the Mito-AZB molecules to the membrane and alternating exposure of the molecules to UV and visible light, mitochondrial membrane potential collapsed, and levels of reactive oxygen species and apoptosis-related proteins surged within the cells. Using fluorescence microscopy, the researchers confirmed the accumulation of the Mito-AZB molecules around mitochondria, validating the targeted activity of Mito-AZB. By replacing the mitochondrial targeting component in the system with other organelle-specific molecules, the researchers were able to adapt the system to target lysosomes and the endoplasmic reticulum. By doing so, they demonstrated the capability of the versatile Mito-AZB system to selectively disrupt various cellular organelles. “This research demonstrates that external light stimuli can precisely manipulate molecular assembly states within cells and modulate cellular responses accordingly,” professor Ryu Ja-Hyoung, who led the research, said. “Such technology holds promise for treating superficial cancers like skin cancer through targeted, noninvasive light therapy. Furthermore, it provides a powerful molecular tool for basic research to transiently inhibit or activate organelle functions, advancing our understanding of cellular mechanisms.” The research was published in Nano Letters (www.doi.org/10.1021/acs.nanolett.5c04030).
