局部表达免疫调节分子可以刺激肿瘤周围微环境中的免疫反应，同时避免与全身给药相关联的毒性。在本研究中，我们开发了一种基于聚乙烯亚胺修饰多孔二氧化硅纳米粒子（PPSN）的载体平台，用于载运细胞因子mRNA进行局部免疫治疗。我们的载体平台在局部mRNA翻译方面显著比FDA批准的脂质纳米颗粒更有效。我们观察到在任何器官中没有靶向外显子翻译的迹象，也没有系统毒性的证据。将细胞因子mRNA负载的PPSN进行肿瘤内注射，可在肿瘤内部产生高水平的蛋白表达，并刺激免疫原性肿瘤细胞死亡。此外，将细胞因子mRNA与免疫检查点抑制剂联合使用，可增强多种小鼠肿瘤模型中的抗癌反应，并实现对远处转移性肿瘤的抑制。我们的结果表明，PPSN介导的mRNA负载具有潜力成为肿瘤免疫治疗中特异、有效和安全的mRNA疗法平台。

Localized expression of immunomodulatory molecules can stimulate immune responses against tumors in the tumor microenvironment while avoiding toxicities associated with systemic administration. In this study, we developed a polyethylenimine-modified porous silica nanoparticle (PPSN)-based delivery platform carrying cytokine mRNA for local immunotherapy in vivo. Our delivery platform was significantly more efficient than FDA-approved lipid nanoparticles for localized mRNA translation. We observed no off-target translation of mRNA in any organs and no evidence of systemic toxicity. Intratumoral injection of cytokine mRNA-loaded PPSNs led to high-level expression of protein within the tumor and stimulated immunogenic cancer cell death. Additionally, combining cytokine mRNA with an immune checkpoint inhibitor enhanced anticancer responses in several murine cancer models and enabled the inhibition of distant metastatic tumors. Our results demonstrate the potential of PPSNs-mediated mRNA delivery as a specific, effective, and safe platform for mRNA-based therapeutics in cancer immunotherapy.