Huang Zixian, Wei Chunfang, Yi Chen, Jiang Qiming, Wang Yong-Qiang, Wang Yan, Xu Tianshu, Lu Nan, Huang Zhiquan, Xu Xiaoding
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China; Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, PR China.
Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangzhou 510120, PR China.
Acta Biomater. 2025 Jan 24;193:429-439. doi: 10.1016/j.actbio.2024.12.061. Epub 2024 Dec 31.
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.
基于自然杀伤（NK）细胞的免疫疗法已成为一种安全有效的癌症治疗方式。然而，治疗益处仅见于血液肿瘤（如白血病），而实体瘤的治疗仍然效果欠佳，这是由于免疫抑制性肿瘤微环境（TME）导致NK细胞在肿瘤组织中的浸润不良及功能障碍。我们在此开发了一种强大的核靶向纳米颗粒（NP）平台，用于全身递送表达gasdermin D N端结构域的质粒（即pGSDMD-N），并增强基于NK细胞的口腔鳞状细胞癌（OSCC）免疫疗法。该纳米平台由聚乙二醇化聚（甲基丙烯酸2-（二异丙基氨基）乙酯）（PDPA）聚合物和可与pGSDMD-N复合的核靶向肽两亲物（NTPA）组成。静脉注射后，该纳米平台可将pGSDMD-N特异性递送至OSCC细胞的细胞核，通过上调GSDMD-N的表达导致细胞焦亡。更重要的是，这种细胞焦亡可通过促进NK细胞向肿瘤组织的募集并增强其活化来增强基于NK细胞的免疫疗法，从而进一步增强pGSDMD-N递送系统的抗癌效果。意义声明：基于NK细胞的免疫疗法在血液肿瘤（如白血病）的治疗方面取得了重大突破，但由于免疫抑制性肿瘤微环境（TME）导致NK细胞功能障碍，其对实体瘤的治疗效果仍然较差。我们在此开发了一种核靶向纳米平台，用于全身递送表达gasdermin D N端结构域的质粒（称为pGSDMD-N），并增强基于NK细胞的口腔鳞状细胞癌（OSCC）免疫疗法。该递送系统不仅可诱导OSCC细胞焦亡，还可促进功能性趋化因子（如CCL3）和细胞因子（如IL-18）的分泌，以增强基于NK细胞的免疫疗法。本文展示的策略可能是增强基于NK细胞的实体瘤免疫疗法的一种有前景的策略。
