Abstract
The development of targeted gene therapies represents a major challenge in oncology that is hampered by delivery issues. Current delivery systems generate many side effects, many of which are due to off-target interactions, and the use of nano-vectors for targeted delivery of siRNA is a promising approach to tackle this challenge. The general objective of this thesis was to design and study original nano-vectors of siRNA for targeting and treating cancer. The first line of research was dedicated to the study of modified peptides for the siRNA delivery. This work aimed to improve the internalization of siRNA in target cells. For this, two types of peptides have been developed: i) CPPs (Cell Penetrating Peptides) functionalized with a targeting sequence derived from laminin ̶ targeting breast cancer cells, and ii) stapled peptides enforcing an α helical secondary structure which endow enhanced stability towards proteolysis and improved cell uptake. The second axis focused on the development of a new generation of nano-vectors obtained by self-assembly. Two strategies have been described: i) a dynamic covalent self-assembly approach to develop Dynamic Covalent Polymers (DCPs) through a siRNA-templated process, and ii) ii) a supramolecular self-assembly approach of cationic porphyrins directed by the templating siRNA. The first strategy led, via functionalization of the DCPs with D-mannose, to the targeted delivery of colorectal cancer cells and the second strategy led to the first example of dual therapy combining siRNA and photodynamic therapy achieved using small molecules.