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TY - THES AU - Ishaqat, Aman Aref Mousa TI - Nucleic acid delivery : from ultrasound-triggered release to autonomous systems PB - RWTH Aachen University VL - Dissertation CY - Aachen M1 - RWTH-2024-05609 SP - 1 Online-Ressource : Illustrationen PY - 2024 N1 - Veröffentlicht auf dem Publikationsserver der RWTH Aachen University N1 - Dissertation, RWTH Aachen University, 2024 AB - Drug delivery plays a crucial role in effectively managing diverse medical conditions. However, conventional systemic drug delivery methods face challenges related to maintaining precise drug concentrations and minimizing side effects. These hurdles can be addressed through the design and refinement of smart responsive drug delivery systems that can be controlled by different types of endogenous and exogenous stimuli.In this work, we present two innovative strategies for achieving controlled on-demand drug delivery, employing ultrasound and enzymes as physical and chemical triggers, respectively. Ultrasound emerges as a standout trigger due to its deep tissue penetration and non-invasive applicability in biological environments, surpassing other physical triggers such as light, magnetic fields and temperature. The unique ability of ultrasound to convert mechanical energy into productive work at the molecular level inspired us to adapt principles developed in the field of polymer mechanochemistry and translate them into biomedical applications. Overcoming the challenge associated with the typically high energy levels of ultrasound in polymer mechanochemistry, we develop a carrier that inherently responds to low-intensity (i.e., spatial-peak temporal-average intensity (IP) below 720 mW∙cm-2) and high frequency (4 -12 MHz) medical imaging US.Our mechanoresponsive drug delivery system, constructed from DNA nanomaterial, serves as a versatile scaffold for delivering various therapeutic nucleic acids, both DNA- and RNA-based. We characterize our system extensively, investigate its mechanical properties and evaluate the underlying mechanism of ultrasound responsiveness. We demonstrate successful delivery of CpG oligodeoxynucleotides leading to controlled immunostimulation in different cell culture models. Moreover, we validate our drug delivery system in healthy animal immunostimulation model in vivo, marking an unprecedented application of polymer mechanochemistry in living organisms. Additionally, we demonstrate the delivery of small interfering RNA oligonucleotides as a second cargo, resulting in controlled gene knockdown in cell culture experiments. We believe that this pioneering work positions our mechanochemically responsive drug delivery system as a universal platform, poised for loading other types of cargo, such as small molecules and proteins, further expanding its potential applications in fundamental and therapeutic research. In the second strategy, our focus is to design DNA circuits that can be activated by the enzymatic activity of exonucleases, facilitating a precise control over the delivery of CpG oligodeoxynucleotides in vitro. These DNA-based nanosystems are pre-programmed to achieve distinct pharmacokinetic profile, characterized with an acute and robust immunostimulatory response, in contrast to a system lacking controlled drug release, which exhibited a slow and delayed response. Furthermore, we transformed the DNA circuit into a dissipative system, characterized by multiple cycles of activation/deactivation, operating out-of-equilibrium. Such systems are envisioned to achieve autonomous control, allowing it to seamlessly interact with and respond to the biological milieu, requiring minimal external intervention. We believe this approach paves the path for tailored drug delivery systems, in which a harmonious interplay between activation and inhibition responses becomes paramount. LB - PUB:(DE-HGF)11 DO - DOI:10.18154/RWTH-2024-05609 UR - https://publications.rwth-aachen.de/record/987345 ER -