Nanoparticle-mediated efficient up-regulation of GSDMD-N to induce pyroptosis and enhance NK cell-based cancer immunotherapy.

Natural killer (NK) cell-based immunotherapy has emerged as a safe and effective therapeutic modality for cancer treatment. However, therapeutic benefits can be only seen in hematological tumors (e.g., leukemia) and the treatment of solid tumors is still less effective due to the immunosuppressive tumor microenvironment (TME)-induced poor infiltration and dysfunction of NK cells in tumor tissues. We herein developed a robust nucleus-targeted nanoparticle (NP) platform for systemic delivery of plasmid expressing the N-terminal domain of GSDMD (i.e., pGSDMD-N) and augment of NK cell-based immunotherapy for oral squamous cell carcinoma (OSCC). This nanoplatform is made of a PEGylated poly(2-(diisopropylamino) ethyl methacrylate) (PDPA) polymer and a nucleus-targeting peptide amphiphile (NTPA) that can complex pGSDMD-N. After intravenous administration, this nanoplatform could specifically deliver pGSDMD-N into the nuclei of OSCC cells, leading to their pyroptosis via up-regulating GSDMD-N expression. More importantly, this pyroptosis could boost NK cell-based immunotherapy via promoting the recruitment of NK cells into tumor tissues and enhancing their activation to further enhance the anticancer effect of the pGSDMD-N delivery system. STATEMENT OF SIGNIFICANCE: : NK cell-based immunotherapy has made a significant breakthrough in the treatment of hematological tumors (e.g., leukemia), but it is still less effective for solid tumors due to immunosuppressive tumor microenvironment (TME)-induced dysfunction of NK cells. We herein developed a nucleus-targeted nanoplatform for systemic delivery of plasmid expressing the N-terminal domain of gasdermin D (denoted pGSDMD-N) and augment of NK cell-based immunotherapy for oral squamous cell carcinoma (OSCC). This delivery system could not only induce the pyroptosis of OSCC cells, but also promote the secretion of functional chemokines (e.g., CCL3) and cytokines (e.g., IL-18) to boost NK cell-based immunotherapy. The strategy demonstrated herein could be a promising strategy to enhance the NK cell-based immunotherapy for solid tumors.