Cytotoxic cell-mediated delivery of nucleic acid nanoparticles as a synergistic cancer immunotherapy

The aim of this project is to merge the benefits of nucleic acid therapeutics and adoptive cell
therapy to develop a synergistic anti-cancer treatment. On the one hand, nucleic acids such as
small interfering RNA (siRNA) are promising anti-cancer drugs as they can specifically down
regulate tumor-promoting genes. To enable in vivo delivery of siRNA, they are typically formulated
in lipid or polymer nanoparticles (NPs). Unfortunately, clinical translation of anti-cancer NPs is still
hampered by poor delivery into the tumor tissue. On the other hand, adoptive cell therapy utilizes
the innate capacity of cytotoxic cells such as cytotoxic T cells and natural killer cells to infiltrate
tumors to induce tumor cell cytolysis. However, despite impressive results in some cancers, many
patients with solid tumors remain refractory to the treatment due to the immunosuppressive
tumor environment that blunts the activity of infiltrating cells. To overcome the limitations of both
therapies, we aim to merge them into a single, synergistic therapy. By covalently anchoring siRNA
NPs to the surface of tumor-migrating cytotoxic cells, we aim to enhance their tumor
accumulation. Next, we will assess if the surface-attached siRNA NPs can be functionally
transferred to immunosuppressive tumor-associated cell types. Finally, by co-encapsulating
immune adjuvants and siRNA targeting the tumor immunosuppressor STAT3, we aim to stimulate
the cytolytic activity of the cytotoxic carrier cells.