Cheng Danling, Luo Libai, Zhang Qin, Song Zheming, Zhan Yiduo, Tu Wenzhi, Li Jingchao, Ma Qiming, Zeng Xianchang
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310009, China.
Oncology Chemotherapy Department, Affiliated Hospital of Youjiang Medical University for Nationalities and Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi of Guangxi Higher Education Institutions, Baise, 533000, China.
Adv Sci (Weinh). 2025 Feb;12(6):e2411739. doi: 10.1002/advs.202411739. Epub 2024 Dec 16.
Various second messengers exert some vital actions in biological systems, including cancer therapy, but the therapeutic efficacy is often need to be improved. A semiconducting polymer nanomessenger (TCa/SPN/a) consisting of two second messengers, calcium ion (Ca) and cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) for metastatic breast cancer therapy, is reported here. Such a TCa/SPN/a is constructed to exhibit X-ray response for the activatable delivery of mitochondria-targeting Ca compound and cGAMP as stimulator of interferon genes (STING) agonist. With X-ray irradiation, TCa/SPN/a could generate singlet oxygen (O) via radiodynamic effect for ablating solid tumors and improving the tumor immunogenicity by inducing immunogenic cell death (ICD). Furthermore, the released mitochondria-targeting Ca compounds show a high binging effect on mitochondria and cause reactive oxygen species (ROS) generation and mitochondria damage via calcium overload, while cGAMP boosts immunological effect through activating STING pathway. In this way, TCa/SPN/a enables a radiodynamic-activated calcium overload and immunotherapy to obviously inhibit the growths of bilateral tumors and also abolish tumor metastasis in metastatic breast cancer mouse models. This article should demonstrate the first smart dual-functional nanotherapeutic containing two second messengers for precise and specific cancer therapy.
多种第二信使在生物系统中发挥着一些至关重要的作用，包括癌症治疗，但治疗效果往往有待提高。本文报道了一种由钙离子（Ca）和环鸟苷单磷酸 - 腺苷单磷酸（cGAMP）这两种第二信使组成的用于转移性乳腺癌治疗的半导体聚合物纳米信使（TCa/SPN/a）。这种TCa/SPN/a被构建用于展示X射线响应，以实现线粒体靶向性Ca化合物的可激活递送以及作为干扰素基因刺激物（STING）激动剂的cGAMP的递送。通过X射线照射，TCa/SPN/a可通过放射动力学效应产生单线态氧（O），用于消融实体肿瘤并通过诱导免疫原性细胞死亡（ICD）提高肿瘤免疫原性。此外，释放的线粒体靶向性Ca化合物对线粒体表现出高结合效应，并通过钙超载导致活性氧（ROS）生成和线粒体损伤，而cGAMP则通过激活STING途径增强免疫效应。通过这种方式，TCa/SPN/a实现了放射动力学激活的钙超载和免疫疗法，能够明显抑制双侧肿瘤的生长，并消除转移性乳腺癌小鼠模型中的肿瘤转移。本文应展示了首个包含两种第二信使用于精确和特异性癌症治疗的智能双功能纳米疗法。
