Optimum genetic delivery for modulating target genes to diseased tissue is a major obstacle for profitable gene therapy. Lipid nanoparticles (LNPs), considered a prospective vehicle for nucleic acid delivery, have demonstrated efficacy in human use during the COVID-19 pandemic. This study introduces a novel biomaterial-based platform, M1-polarized macrophage-derived cellular nanovesicle-coated LNPs (M1-C-LNPs), specifically engineered for a combined gene-immunotherapy approach against solid tumor. The dual-function system of M1-C-LNPs encapsulates -targeting siRNA within LNPs and immune-modulating cytokines within M1 macrophage-derived cellular nanovesicles (M1-NVs), effectively facilitating apoptosis in cancer cells without impacting T and NK cells, which activate the intratumoral immune response to promote granule-mediating killing for solid tumor eradication. Enhanced retention within tumor was observed upon intratumoral administration of M1-C-LNPs, owing to the presence of adhesion molecules on M1-NVs, thereby contributing to superior tumor growth inhibition. These findings represent a promising strategy for the development of targeted and effective nanoparticle-based cancer genetic-immunotherapy, with significant implications for advancing biomaterial use in cancer therapeutics.

中文翻译：

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M1 极化巨噬细胞衍生的细胞纳米囊泡包被的脂质纳米粒子，通过基因疗法和癌症免疫疗法的杂交增强癌症治疗

将靶基因调节到患病组织的最佳基因传递是基因治疗盈利的主要障碍。脂质纳米颗粒 (LNP) 被认为是一种有前景的核酸输送载体，已在 COVID-19 大流行期间证明了其在人类使用中的有效性。这项研究介绍了一种基于新型生物材料的平台，即 M1 极化巨噬细胞衍生的细胞纳米囊泡包被的 LNP（M1-C-LNP），专门针对实体瘤的基因-免疫联合治疗方法而设计。M1-C-LNP 的双功能系统将靶向 siRNA 封装在 LNP 内，并将免疫调节细胞因子封装在 M1 巨噬细胞衍生的细胞纳米囊泡 (M1-NV) 内，有效促进癌细胞凋亡，而不影响 T 细胞和 NK 细胞，从而激活 T 细胞和 NK 细胞。瘤内免疫反应促进颗粒介导的杀伤，从而根除实体瘤。由于 M1-NV 上存在粘附分子，在肿瘤内施用 M1-C-LNP 后观察到在肿瘤内的保留增强，从而有助于优异的肿瘤生长抑制。这些发现代表了开发基于纳米颗粒的靶向且有效的癌症遗传免疫疗法的有前景的策略，对于推进生物材料在癌症治疗中的使用具有重大意义。