Zhejiang Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China.
School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
ACS Appl Mater Interfaces. 2024 Sep 18;16(37):49053-49068. doi: 10.1021/acsami.4c09830. Epub 2024 Sep 6.
Immunotherapy has been extensively utilized and studied as a prominent therapeutic strategy for tumors. However, the presence of a hypoxic immunosuppressive tumor microenvironment significantly reduces the efficacy of the treatment, thus impeding its application. In addition, the hypoxic microenvironment can also lead to the enrichment of immunosuppressive cells and reduce the effectiveness of tumor immunotherapy; nanoparticles with biocatalytic activity have the ability to relieve hypoxia in tumor tissues and deliver drugs to target cells and have been widely concerned and applied in the field of tumor therapy. The present study involved the development of a dual nanodelivery system that effectively targets the immune system to modify the tumor microenvironment (TME). The nanodelivery system was developed by incorporating R848 and Imatinib (IMT) into Pt nanozyme loaded hollow polydopamine (P@HP) nanocarriers. Subsequently, their surface was modified with specifically targeted peptides that bind to M2-like macrophages and regulatory T (Treg) cells, thereby facilitating the precise targeting of these cells. When introduced into the tumor model, the nanocarriers were able to selectively target immune cells in tumor tissue, causing M2-type macrophages to change into the M1 phenotype and reducing Treg activation within the tumor microenvironment. In addition, the carriers demonstrated exceptional biocatalytic activity, effectively converting HO into oxygen and water at the tumor site while the drug was active, thereby alleviating the hypoxic inhibitory conditions present in the tumor microenvironment. Additionally, this further enhanced the infiltration of M1-type macrophages and cytotoxic T lymphocytes. Moreover, when used in conjunction with immune checkpoint therapy, the proposed approach demonstrated enhanced antitumor immunotherapeutic effects. The bimodal targeted immunotherapeutic strategy developed in the present study overcomes the drawbacks of traditional immunotherapy approaches while offering novel avenues for the treatment of cancer.
免疫疗法已被广泛应用和研究，作为治疗肿瘤的主要策略。然而，缺氧免疫抑制性肿瘤微环境的存在显著降低了治疗效果，从而限制了其应用。此外，缺氧微环境还会导致免疫抑制细胞的富集，降低肿瘤免疫治疗的效果；具有生物催化活性的纳米粒子能够缓解肿瘤组织中的缺氧，并将药物递送到靶细胞，因此在肿瘤治疗领域受到广泛关注和应用。本研究开发了一种双重纳米递药系统，能够有效地靶向免疫系统，从而改善肿瘤微环境（TME）。该纳米递药系统通过将 R848 和伊马替尼（IMT）整合到负载铂纳米酶的中空聚多巴胺（P@HP）纳米载体中而构建。随后，通过特定的靶向肽对其表面进行修饰，这些肽能够与 M2 样巨噬细胞和调节性 T（Treg）细胞结合，从而实现对这些细胞的精确靶向。当将纳米载体引入肿瘤模型中时，它们能够选择性地靶向肿瘤组织中的免疫细胞，使 M2 型巨噬细胞转变为 M1 表型，并减少肿瘤微环境中 Treg 的激活。此外，这些载体表现出卓越的生物催化活性，能够在药物活性的情况下，有效地将 HO 转化为氧气和水，从而缓解肿瘤微环境中存在的缺氧抑制条件。此外，这进一步增强了 M1 型巨噬细胞和细胞毒性 T 淋巴细胞的浸润。此外，当与免疫检查点治疗联合使用时，所提出的方法显示出增强的抗肿瘤免疫治疗效果。本研究中开发的双模态靶向免疫治疗策略克服了传统免疫治疗方法的缺点，为癌症治疗提供了新的途径。
