Department of Laboratory Medicine, Huazhong University of Science and Technology Union Shenzhen Hospital (Nanshan Hospital), Shenzhen University, Shenzhen, 518052, People's Republic of China.
Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, 518060, People's Republic of China.
J Nanobiotechnology. 2024 Jun 19;22(1):348. doi: 10.1186/s12951-024-02612-3.
Tumor-associated macrophages (TAMs) are a promising target for cancer immunotherapy, but delivering therapeutic agents to TAMs within the tumor microenvironment (TME) is challenging. In this study, a photosensitive, dual-targeting nanoparticle system (M.RGD@Cr-CTS-siYTHDF1 NPs) was developed. The structure includes a shell of DSPE-modified RGD peptides targeting integrin receptors on tumor cells and carboxymethyl mannose targeting CD206 receptors on macrophages, with a core of chitosan adsorbing m6A reading protein YTHDF1 siRNA and chromium nanoparticles (Cr NPs). The approach is specifically designed to target TAM and cancer cells, utilizing the photothermal effect of Cr NPs to disrupt the TME and deliver siYTHDF1 to TAM. In experiments with tumor-bearing mice, M.RGD@Cr-CTS-siYTHDF1 NPs, when exposed to laser irradiation, effectively killed tumor cells, disrupted the TME, delivered siYTHDF1 to TAMs, silenced the YTHDF1 gene, and shifted the STAT3-STAT1 equilibrium by reducing STAT3 and enhancing STAT1 expression. This reprogramming of TAMs towards an anti-tumor phenotype led to a pro-immunogenic TME state. The strategy also suppressed immunosuppressive IL-10 production, increased expression of immunostimulatory factors (IL-12 and IFN-γ), boosted CD8 + T cell infiltration and M1-type TAMs, and reduced Tregs and M2-type TAMs within the TME. In conclusion, the dual-targeting M.RGD@Cr-CTS-siYTHDF1 NPs, integrating dual-targeting capabilities with photothermal therapy (PTT) and RNA interference, offer a promising approach for molecular targeted cancer immunotherapy with potential for clinical application.
肿瘤相关巨噬细胞（TAMs）是癌症免疫治疗的一个有前途的靶点，但在肿瘤微环境（TME）中向 TAMs 递送治疗剂具有挑战性。在这项研究中，开发了一种光敏、双靶向纳米颗粒系统（M.RGD@Cr-CTS-siYTHDF1 NPs）。该结构包括靶向肿瘤细胞整合素受体的 DSPE 修饰的 RGD 肽的壳层和靶向巨噬细胞 CD206 受体的羧甲基甘露糖，以及壳聚糖吸附 m6A 阅读蛋白 YTHDF1 siRNA 和铬纳米颗粒（Cr NPs）的核。该方法专门设计用于靶向 TAM 和癌细胞，利用 Cr NPs 的光热效应破坏 TME 并将 siYTHDF1 递送至 TAM。在荷瘤小鼠实验中，M.RGD@Cr-CTS-siYTHDF1 NPs 在激光照射下，有效杀死肿瘤细胞，破坏 TME，将 siYTHDF1 递送至 TAMs，沉默 YTHDF1 基因，并通过降低 STAT3 和增强 STAT1 表达来改变 STAT3-STAT1 平衡。这种对 TAM 的重编程向抗肿瘤表型转变导致了一种促免疫原性的 TME 状态。该策略还抑制了免疫抑制性 IL-10 的产生，增加了免疫刺激因子（IL-12 和 IFN-γ）的表达，增强了 CD8+T 细胞浸润和 M1 型 TAMs，减少了 TME 中的 Tregs 和 M2 型 TAMs。总之，双靶向 M.RGD@Cr-CTS-siYTHDF1 NPs 将双靶向能力与光热治疗（PTT）和 RNA 干扰相结合，为具有临床应用潜力的分子靶向癌症免疫治疗提供了一种有前途的方法。
