Gene therapy has potential therapeutic applications for the treatment of many diseases like cancer, monogenetic diseases, vascular disease, among others. Although the majority of protocols in gene therapy employ viral vectors due to their high transfection efficiency, increasing concerns about their immunological response prompts the development of safe and effective non-viral delivery systems. Poly(?-aminoester)s (pBAEs) are promising non-viral vectors due to their polyester nature results in an attractive biocompatible profile due to their high biodegradability and reduced toxicity. Here we present a novel family of pBAEs, which incorporate terminal oligopeptides, capable of condensing both DNA and siRNA into particles with nanometric size. Firstly, in vitro experiments were performed to evaluate the ability of this new pBAEs to efficient delivery both DNA and siRNA, for up- and down-regulation of a target gene, respectively. Results demonstrated that the oligopeptide incorporation at the termini of pBAEs improved transfection efficiency and biocompatibility when compared to basic pBAEs and commercially available transfection agents. Moreover, nanoparticles prepared with this new family of pBAEs showed different intracellular localization, such as perinuclear or cytoplasmatic, depending on the oligopeptide composition. In addition, specific formulation of pBAEs showed different transfection efficiency depending on the cell line, which revealed that chemical composition of the oligopeptides have a deep effect on transfection. Secondly, siRNA-pBAEs nanoparticles were succesfullly incorporated into hydrogel scaffold for local and sustained release of siRNA. Release studies demonstrated that siRNA was sustainably released due to nanoparticle stabilization within the hydrogel. Finally, in vivo results demonstrated that the local delivery system proposed here was able to silence luciferase expression, in a murine breast cancer model, over a long period of time achieving higher silencing efficiency than a commercial in vivo transfection agent.
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