RNA Nanoparticles-Displaying Exosomes to enhance targeted siRNA delivery for Prostate Cancer treatment.

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PROJECT SUMMARY Prostate Cancer is the most common type of cancer diagnosed in the male population and the sixth cause of death every year. While different therapeutic strategies are available for the clinical management of the disease (surgery, radiation therapy, chemotherapy, hormonal therapy) research is shifting to innovative approaches based on the delivery of RNA interfering agents, including small interfering RNA (siRNA). Despite their efficacy in promoting tumor suppression, siRNA-based strategies are negatively affected by poor delivery of siRNA, short half-life in vivo, and alteration of the immune response, which hinder their translation into clinical practice. Exosomes have been proposed as delivery nanoparticles thanks to their natural involvement in intercellular transport of protein and nucleic acids. However, exosomes suffer from technical limitations (low targeting efficiency, poor biodistribution, endosome trapping). ExonanoRNA proposes a novel approach based on RNA Nanotechnology to generate RNA Nanoparticles-Displaying Exosomes for the targeted delivery of siRNA in prostate cancer cells. The use of RNA nanoparticles associated with exosomes allows superior cell targeting and efficient delivery of siRNA. Exosomes are engineered to display a favorable pharmacokinetic profile and low immunogenicity and to avoid endosome trapping. The company has preliminary validated the use of nanoparticle orientation to control RNA loading and ligand display on exosomes in a proof-of-concept study that supports the use of RNA nanoparticles- loaded Exosomes to target prostate cancer. In this SBIR Phase I project, ExonanoRNA will generate lead candidates with high level of stability, production efficiency, therapeutic efficacy, and safety suitable for clinical testing. This goal will be achieved through two aims. Aim 1) selection of the most appropriate targeting ligand to ensure the maximum specificity to prostate cells and identification of the optimal number of RNA NPs associated to the EVs to achieve the most efficient targeting efficiency. Aim 2) The best candidate will be tested in vitro on human prostate adenocarcinoma (LNCaP+) cells, and in vivo on xenografts mice to investigate efficacy, and safety. The proposed activities will lead to a Phase II project where ExonanoRNA foresees the scale up of production of the validated candidate and perform IND- enabling studies in small and large animals (rat, beagle dog).