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Title
Photoswitchable molecular gene delivery systems
Abstract
Nucleic acids have, in recent years, emerged as a class of therapeutic agents due to their significant potential in medicine. However, their intrinsic instability—stemming from rapid degradation by nucleases and cellular defense mechanisms—highlights the need for the development of gene delivery systems capable of compacting and protecting genetic material, while also enabling precise targeting of NATs across extracellular and intracellular barriers.
In the pursuit of technologies that provide spatiotemporal control over these delivery systems, multiple strategies have been explored. In particular, the use of light as an external stimulus has gained considerable attention. Light-responsive systems incorporating photoswitches allow modulation of the physicochemical properties of the delivery vector upon irradiation, thereby enabling controlled activation of gene transport processes.
Within this context, this doctoral thesis— developed within the framework of a cotutelle between research groups specialized in gene delivery systems and photopharmacology—offers the opportunity to explore this strategy across different platforms. On the one hand, Chapter II investigates two families of compounds—azobenzene-based ionizable amphiphilic Janus dendrimers (azo-IAJDs) and azobenzene-based ionizable dendrimers (azo-IDs)—as single-component carriers for plasmid DNA (pDNA). In both families, a variety of cationic headgroups were introduced to study the interaction and complexation mechanisms between the molecular vector and pDNA. Additionally, the impact of E/Z isomerization on nanoparticle architecture was examined, revealing optomechanical modulation that influences system properties at both the micro- and macroscale, as reflected in in vitro and in vivo performance.
On the other hand, Chapter III focuses on a family of azobenzene derivatives—Host–Guest Supramolecular Ionizable Amphiphiles (azo-SIAs). In this system, the E isomer is capable of forming an inclusion complex with a lipid-modified cyclodextrin, yielding a supramolecular amphiphilic vector able to complex and protect pDNA. In contrast, the Z isomer is unable to aggregate, thereby enabling light-triggered activation of the nanoparticle system.
PhD supervision
- Co-director: Pr. Joanne Xie, Professor, ENS Paris-Saclay
- Co-director: Pr. Carmen Ortiz-Mellet, Professor, Facultad de Química, University of Sevilla
Members of the jury
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Antonio Vargas Berenguel, Professor, Departamento de Química y Física, University of Almeria, Reviewer
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Matthieu Sollogoub, Professor, IPCM, Sorbonne University, Reviewer
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Sandrine Piguel, Professor, BioCIS, Paris-Saclay University, Examiner
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Elena Sánchez Fernández, Professor, Departamento de Química Orgánica, University of Sevilla, Examiner
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José Luis De Paz Carrera, Professor, Spanish National Research Council (CSIC), Examiner