Targeting Accessories to the Crime: Nanoparticle Nucleic Acid Delivery to the Tumor Microenvironment

Nucleic acid delivery for cancer holds extraordinary promise. Increasing expression of tumor suppressor genes or inhibition of oncogenes in cancer cells has important therapeutic potential. However, several barriers impair progress in cancer gene delivery. These include effective delivery to cancer cells and relevant intracellular compartments. Although viral gene delivery can be effective, it has the disadvantages of being immuno-stimulatory, potentially mutagenic and lacking temporal control. Various nanoparticle (NP) platforms have been developed to overcome nucleic acid delivery hurdles, but several challenges still exist. One such challenge has been the accumulation of NPs in non-cancer cells within the tumor microenvironment (TME) as well as the circulation. While uptake by these cancer-associated cells is considered to be an off-target effect in some contexts, several strategies have now emerged to utilize NP-mediated gene delivery to intentionally alter the TME. For example, the similarity of NPs in shape and size to pathogens promotes uptake by antigen presenting cells, which can be used to increase immune stimulation and promote tumor killing by T-lymphocytes. In the era of immunotherapy, boosting the ability of the immune system to eliminate cancer cells has proven to be an exciting new area in cancer nanotechnology. Given the importance of cancer-associated cells in tumor growth and metastasis, targeting these cells in the TME opens up new therapeutic applications for NPs. This review will cover evidence for non-cancer cell accumulation of NPs in animal models and patients, summarize characteristics that promote NP delivery to different cell types, and describe several therapeutic strategies for gene modification within the TME.