Gong Jiali, Cheng Danling, Liu Changcun, Wu Shan, Sun Na, Zhao Lingzhou, Li Jingchao, Xing Yan, Zhao Jinhua
Department of Nuclear Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Biological Science and Medical Engineering, Donghua University, Shanghai, 201620, China.
Adv Healthc Mater. 2025 Jan;14(3):e2404184. doi: 10.1002/adhm.202404184. Epub 2024 Nov 21.
Tumor immunotherapy represents a highly promising modality for the treatment of triple-negative breast cancer (TNBC). Nevertheless, its therapeutic efficacy has been profoundly impacted by challenges such as low drug uptake, hypoxia, and immunosuppression. To address these problems, the study develops a strategy combining sonodynamic therapy (SDT) and immunotherapy using biomimetic nanoparticles coated with hybrid membranes. The nanoparticles are loaded with semiconducting polymers (PFODBT), Atovaquone (ATO), and TMP195 to enhance biocompatibility, targeting ability, and drug uptake and retention at the tumor site. In in vitro experiments, the biomimetic nanoparticles alleviate hypoxia, induce immunogenic cell death (ICD), and prompt reprogramming of tumor-associated macrophages (TAMs) from M2 type to M1 type. In in vivo experiments, the synergistic effects of enhanced SDT-mediated ICD and TAMs repolarization significantly inhibit the proliferation of primary and distant tumor in the 4T1 subcutaneous tumor model, and effectively attenuated metastasis of lung and liver. Moreover, the in vivo immune responses are further activated by improving the maturation of dendritic cells, filtration of CD8 T cells, and depletion of regulatory T cells. This study offers a novel strategy for TNBC therapy by converting the tumor microenvironment from the "cold" into "hot" tumor through multiple synergistic therapies.
肿瘤免疫疗法是治疗三阴性乳腺癌（TNBC）极具前景的一种方式。然而，其治疗效果受到诸如药物摄取率低、缺氧和免疫抑制等挑战的深刻影响。为解决这些问题，该研究开发了一种将声动力疗法（SDT）与免疫疗法相结合的策略，使用涂有混合膜的仿生纳米颗粒。纳米颗粒负载有半导体聚合物（PFODBT）、阿托伐醌（ATO）和TMP195，以增强生物相容性、靶向能力以及在肿瘤部位的药物摄取和保留。在体外实验中，仿生纳米颗粒缓解缺氧，诱导免疫原性细胞死亡（ICD），并促使肿瘤相关巨噬细胞（TAM）从M2型重编程为M1型。在体内实验中，增强的SDT介导的ICD和TAM重极化的协同效应显著抑制4T1皮下肿瘤模型中原发肿瘤和远处肿瘤的增殖，并有效减弱肺和肝的转移。此外，通过改善树突状细胞的成熟、CD8 T细胞的筛选以及调节性T细胞的消耗，进一步激活体内免疫反应。这项研究通过多种协同疗法将肿瘤微环境从“冷”肿瘤转变为“热”肿瘤，为TNBC治疗提供了一种新策略。
