Department of Medical Imaging, Third Affiliated Hospital of Southern Medical University (Academy of Orthopedics Guangdong Province), Southern Medical University, Guangzhou, Guangdong 510630, P. R. China.
Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, P. R. China.
ACS Biomater Sci Eng. 2023 Feb 13;9(2):773-783. doi: 10.1021/acsbiomaterials.2c01287. Epub 2023 Jan 4.
Cancer nanomedicine combined with immunotherapy has emerged as a promising strategy for the treatment of cancer. However, precise regulation of the activation of antitumor immunity in targeting tissues for safe and effective cancer immunotherapy remains challenging. Herein, we report a tumor acidic microenvironment-responsive promodulator iron oxide nanoparticle (termed as FGR) with pH-activated action for photothermal-enhanced chemodynamic immunotherapy of cancer. FGR is formed via surface-modifying iron oxide nanoparticles with a dextran-conjugated Toll-like receptor agonist (R848) containing an acid-labile bond. In an acidic tumor microenvironment, the acid-responsive bonds are hydrolyzed to trigger the specific release of R848 to promote the maturation of dendritic cells. In addition, iron oxide nanoparticles within FGR exert photothermal and chemodynamic effects under near-infrared laser irradiation to directly kill tumor cells and induce immunogenic cell death. The synergistic effect of the released immunogenic factors and the acid-activated TLR7/8 pathway stimulates the formation of strong antitumor immunity, resulting in increased infiltration of cytotoxic CD8 T cells into tumor tissues. As a result, FGR achieves acid-responsive on-demand release and activation of modulators in tumor sites and mediates photothermal-enhanced chemodynamic immunotherapy to inhibit the growth and metastasis of melanoma. Therefore, this work proposes a general strategy for designing prodrug nanomedicines to accurately regulate cancer immunotherapy.
癌症纳米医学与免疫疗法相结合，已成为治疗癌症的一种有前途的策略。然而，在靶向组织中精确调节抗肿瘤免疫的激活以实现安全有效的癌症免疫治疗仍然具有挑战性。在此，我们报告了一种肿瘤酸性微环境响应型促动氧化铁纳米颗粒（称为 FGR），它具有 pH 激活作用，可用于癌症的光热增强化学动力学免疫治疗。FGR 通过用含有酸不稳定键的葡聚糖偶联 Toll 样受体激动剂（R848）修饰氧化铁纳米颗粒形成。在酸性肿瘤微环境中，酸响应键被水解以触发 R848 的特异性释放，从而促进树突状细胞的成熟。此外，FGR 内的氧化铁纳米颗粒在近红外激光照射下发挥光热和化学动力学效应，直接杀死肿瘤细胞并诱导免疫原性细胞死亡。释放的免疫原性因子和酸激活的 TLR7/8 途径的协同作用刺激了强大的抗肿瘤免疫的形成，导致细胞毒性 CD8 T 细胞更多地浸润到肿瘤组织中。结果，FGR 实现了在肿瘤部位按需释放和调节剂的酸响应激活，并介导光热增强化学动力学免疫治疗以抑制黑色素瘤的生长和转移。因此，这项工作提出了一种设计前药纳米药物的通用策略，以精确调节癌症免疫治疗。
