纳米颗粒介导的 GSDMD-N 高效上调诱导焦亡并增强基于 NK 细胞的癌症免疫治疗

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.