Stimuli-Responsive Self-Assembly Strategies for Spatiotemporal Modulation of Organelle Targeting Therapy

Abstract

Supramolecular systems, formed through non-covalent interactions, are pivotal in mimicking the dynamic, self-organizing behavior of biological macromolecules such as proteins, nucleic acids, and lipids. These systems play a crucial role in cellular functions by enabling the precise regulation of biomolecular interactions that govern physiological processes. The diversity and adaptability of supramolecular chemistry allow for the design of systems that respond to specific biological stimuli, creating potential therapeutic strategies that address disease mechanisms. At the heart of this approach is the ability to control self-assembly processes, enabling the creation of functional nanostructures that interact with cellular components in a targeted manner. This versatility has led to the exploration of stimuli-responsive supramolecular systems that undergo structural transitions or reorganizations in response to internal cues, such as redox conditions or enzyme activity, as well as external signals like light. By leveraging these mechanisms, such systems can be tailored to selectively activate therapeutic interventions in diseased tissues, where microenvironmental conditions are significantly altered. This thesis explores two innovative approaches to leveraging supramolecular chemistry for therapeutic applications, focusing on stimuli-responsive systems. Chapter 2 focuses on an AIE-based monomer system that modulates mitochondrial dynamics via light-induced fission and fusion processes. Light exposure triggers AIE-induced ROS, which induce disulfide bond formation, leading to PISA inside mitochondria. This process results in the formation of nanostructures, inducing mitochondrial fission. Subsequent washing with fresh media restores mitochondria to their original state, suggesting a novel approach for controlling mitochondrial dynamics in response to external stimuli. The ability to manipulate mitochondrial morphology and function through this system offers potential therapeutic applications in diseases related to mitochondrial dysfunction. Chapter 3 develops a Transformable LYTAC system that utilizes enzyme-responsive self-assembly to enhance the degradation of pathological proteins. In this system, micelles undergo a transformation into fiber structures upon activation by ALP. This transformation increases the interaction range with target proteins and lysosome receptors, resulting in multi-interaction and high affinity, thereby enhancing the efficiency of TPD. The ability to switch between different self-assembled structures offers a mechanism for more effective targeting of disease-related proteins, presenting potential therapeutic applications for diseased or aging cells.