Background
DNA origami nanoparticle (DoriNano) harnesses the power of nucleic acid nanotechnology to revolutionize therapeutic cargo delivery with unparalleled precision at the nanoscale. Overcoming the limitations that have plagued traditional nanoparticle-based delivery systems, the DoriNano platform offers an array of advantages, including ease of manufacturing, stability and easy storage, ease of formulation, simple characterization, high drug loading capacity, control of release kinetics, minimal off-target effects, low immunogenicity, programable size and shape, and precise nanospacing/stoichiometry controls. These distinct benefits empower us to develop a new generation of safe, effective, and cost-efficient combination nanomedicines, delivering therapeutic cargos with precise cellular targeting at minimal effective dose for a wide range of severe diseases.
Methods
Our patented nanotechnology platform has propelled the development of innovative combinational cancer immunotherapies that activate the body’s immune responses against various forms of cancer. These therapies have demonstrated remarkable efficacy across a spectrum of mouse subcutaneous tumor models, including melanoma, colon carcinoma, lung cancer, lymphoma, and neuroblastoma (part of the work was published in Nature Nanotechnology). The DoriNano in this case consists of a combination of minimal effective dose of tumor antigens and adjuvant at optimal nanoscale spacing, which cured cancers in multiple mice when combined with an immune checkpoint blockade anti-PD-L1 antibody. We have conducted extensive immune profiling using flow cytometry, ELISA, ELISpot, and Luminex to study cell activation in the immune system and tumor tissue.
Results
In general, the mice treated with DNA origami nanoparticle vaccine (DoriVac) showed significant low tumor burden and prolonged mouse survival. We observed that DoriVac enhanced DC activation, antigen cross-presentation, CD8+ T cell activation, Th1-polarized CD4+ activation and natural killer cell activation. The versatility of our plug-and-play strategy is further exemplified by its potential as a prophylactic vaccine in infectious disease settings. The DoriVac, conjugated with highly conserved infectious-disease-specific HR2 peptides and CpG adjuvant at precise nanoscale spacing, induced neutralizing antibodies, Th1-polarized CD4+ T cells, and CD8+ T cells in naïve mice, with significant improvement over a bolus control.
Conclusions
In conclusion, we have developed a highly effective cancer therapeutic vaccine with significant potential for clinical translation. Furthermore, we envision the rapid and convenient loading of patient-specific antigens/neoantigens onto prefabricated, adjuvant-containing DNA origami to create personalized cancer vaccines that can be easily combined with FDA-approved immune checkpoint inhibitors. This technology platform also holds promise for investigating other cellular ligand-receptor interactions where nanoscale ligand spacing critically influences receptor signaling and subsequent immune polarization.