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通过级联热休克蛋白和炎症抑制实现肿瘤低温光热免疫治疗的自递送纳米疗法

Self-Delivery Nanotherapeutics for Tumor Low-Temperature Photothermal Immunotherapy through Cascade Heat Shock Protein and Inflammation Inhibition.

作者信息

Deng Xiaoliang, Feng Xianquan, Tang Xiaohui, Zheng Zhihui, Zheng Da, Zheng Enqin, Zeng Lingjun, Xu Shiying, Chen Boxin, Zhang Qian, Liu Zhihong, Song Hongtao

机构信息

School of Pharmacy, Fujian University of Chinese Traditional Medicine, Fuzhou 350122, China.

900th Hospital of PLA Joint Logistic Support Force, Fuzhou 350025, China.

出版信息

ACS Appl Mater Interfaces. 2025 Aug 13;17(32):45579-45597. doi: 10.1021/acsami.5c10905. Epub 2025 Jul 30.

Abstract

The clinical efficacy of immunotherapy in triple-negative breast cancer (TNBC) faces dual barriers: poor immunogenicity and a suppressive tumor microenvironment. While low-temperature photothermal therapy (LTPTT) has emerged as a potential immunostimulatory strategy, its efficacy is counteracted by heat shock protein (HSP) induction and COX-2/PGE2-mediated immunosuppression. To address these challenges, we developed a multifunctional immunophotothermal nanoplatform (IAC NPs) through rational engineering of human serum albumin for combinatorial delivery of indocyanine green as a photothermal converter, atovaquone for HSP70-mediated thermoresistance blockade, and celecoxib for COX-2/PGE2 pathway inhibition. The IAC NPs achieved tumor-targeted delivery and NIR-activated immunogenic phototherapy while coinhibiting HSP70 (via atovaquone's mitochondrial complex III blockade) and the COX-2/PGE2 immunosuppressive axis (via celecoxib). The triple medications' synergistic action improved the expression of effector memory T cells, boosted the maturation of dendritic cells, encouraged the infiltration of CD4+ and CD8+ T cells, and reduced regulatory T cells. In vivo, the IAC NPs mediated profound suppression of both primary tumors and metastatic dissemination while exhibiting optimal biocompatibility for clinical translation. Our work validates a nanoenabled self-delivery system that augments the efficacy of LTPTT immunotherapy against TNBC by orchestrating coordinated inhibition of HSPs and inflammatory responses.

摘要

免疫疗法在三阴性乳腺癌(TNBC)中的临床疗效面临双重障碍:免疫原性差和肿瘤微环境抑制。虽然低温光热疗法(LTPTT)已成为一种潜在的免疫刺激策略,但其疗效被热休克蛋白(HSP)诱导和COX-2/PGE2介导的免疫抑制所抵消。为应对这些挑战,我们通过对人血清白蛋白进行合理工程设计,开发了一种多功能免疫光热纳米平台(IAC NPs),用于联合递送吲哚菁绿作为光热转换器、阿托伐醌用于HSP70介导的热抗性阻断以及塞来昔布用于COX-2/PGE2途径抑制。IAC NPs实现了肿瘤靶向递送和近红外激活的免疫原性光疗,同时共同抑制HSP70(通过阿托伐醌阻断线粒体复合物III)和COX-2/PGE2免疫抑制轴(通过塞来昔布)。三种药物的协同作用提高了效应记忆T细胞的表达,促进了树突状细胞的成熟,促进了CD4+和CD8+ T细胞的浸润,并减少了调节性T细胞。在体内,IAC NPs介导了对原发性肿瘤和转移扩散的深度抑制,同时展现出对临床转化的最佳生物相容性。我们的工作验证了一种纳米级自递送系统,该系统通过协调抑制热休克蛋白和炎症反应,增强了LTPTT免疫疗法对TNBC的疗效。

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