Yi Hongyang, Wang Zhuyao, Li Xiaojiao, Yin Min, Wang Lihua, Aldalbahi Ali, El-Sayed Nahed Nasser, Wang Hui, Chen Nan, Fan Chunhai, Song Haiyun
1. Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of sciences, Shanghai 200031, China; 2. Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100021, China.
3. Division of Physical Biology and Bioimaging Center, Shanghai Synchrotron Radiation Facility, CAS Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, China.
Theranostics. 2016 Jul 18;6(11):1810-20. doi: 10.7150/thno.16127. eCollection 2016.
Many types of biocompatible nanomaterials have proven of low cytotoxicity and hold great promise for various applications in nanomedicine. Whereas they generally do not cause apparent organ toxicity or tissue damage in adult animals, it is yet to determine their biological consequences in more general contexts. In this study, we investigate how silica nanoparticles (NPs) affect cellular activities and functions under several physiological or pathological conditions. Although silica NPs are generally regarded as "inert" nanocarriers and widely employed in biomedical studies, we find that they actively affect Wnt signaling in various types of cell lines, diminishing its anti-adipogenic effect in preadipocytes and pro-invasive effect in breast cancer cells, and more significantly, impair Wnt-regulated embryonic development in Zebrafish. We further demonstrate that intracellular silica NPs block Wnt signal transduction in a way resembling signaling molecules. Specifically, silica NPs target the Dvl protein, a key component of Wnt signaling cascade, for lysosomal degradation. As Wnt signaling play significant roles in embryonic development and adipogenesis, the observed physiological effects beyond toxicity imply potential risk of obesity, or developmental defects in somitogenesis and osteogenesis upon exposure to silica NPs. In addition, given the clinical implications of Wnt signaling in tumorigenesis and cancer metastasis, our work also establishes for the first time a molecular link between nanomaterials and the Wnt signaling pathway, which opens new door for novel applications of unmodified silica NPs in targeted therapy for cancers and other critical illness.
许多类型的生物相容性纳米材料已被证明具有低细胞毒性，并在纳米医学的各种应用中具有巨大潜力。虽然它们通常不会在成年动物中引起明显的器官毒性或组织损伤，但在更广泛的背景下，其生物学后果仍有待确定。在本研究中，我们研究了二氧化硅纳米颗粒（NPs）在几种生理或病理条件下如何影响细胞活性和功能。尽管二氧化硅纳米颗粒通常被视为“惰性”纳米载体并广泛应用于生物医学研究，但我们发现它们会积极影响各种细胞系中的Wnt信号传导，削弱其在前脂肪细胞中的抗脂肪生成作用和在乳腺癌细胞中的促侵袭作用，更重要的是，损害斑马鱼中Wnt调节的胚胎发育。我们进一步证明，细胞内二氧化硅纳米颗粒以类似于信号分子的方式阻断Wnt信号转导。具体而言，二氧化硅纳米颗粒靶向Wnt信号级联的关键成分Dvl蛋白，使其进行溶酶体降解。由于Wnt信号传导在胚胎发育和脂肪生成中起重要作用，观察到的除毒性外的生理效应意味着暴露于二氧化硅纳米颗粒后存在肥胖风险或在体节发生和骨生成中出现发育缺陷的潜在风险。此外，鉴于Wnt信号传导在肿瘤发生和癌症转移中的临床意义，我们的工作还首次建立了纳米材料与Wnt信号通路之间的分子联系，这为未修饰的二氧化硅纳米颗粒在癌症和其他严重疾病的靶向治疗中的新应用打开了新的大门。
