Silica Nanoparticles Target a Wnt Signal Transducer for Degradation and Impair Embryonic Development in Zebrafish.
Silica Nanoparticles Target a Wnt Signal Transducer for Degradation and Impair Embryonic Development in Zebrafish.
复制标题
二氧化硅纳米颗粒靶向 Wnt 信号转导器降解并损害斑马鱼胚胎发育
作者：
Yi H;Wang Z;Li X;Yin M;Wang L;Aldalbahi A;El-Sayed NN;Wang H;Chen N;Fan C;Song H
许多类型的生物相容纳米材料已被证明具有低细胞毒性，并在纳米医学中具有广泛的应用前景。虽然它们通常不会对成年动物造成明显的器官毒性或组织损伤，但在更广泛的背景下，尚未确定它们的生物学后果。在这项研究中，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的活动和功能。虽然二氧化硅纳米颗粒通常被认为是惰性纳米载体，并被广泛应用于生物医学研究，但我们发现它们积极地影响各种类型的细胞系中的Wnt信号，减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Wnt调控的斑马鱼胚胎发育。我们进一步证明，细胞内的二氧化硅纳米颗粒以一种类似于信号分子的方式阻止Wnt信号转导。具体地说，二氧化硅纳米粒以DVL蛋白为靶点，DVL蛋白是Wnt信号级联的关键组成部分，用于溶酶体降解。由于Wnt信号在胚胎发育和脂肪形成中起重要作用，所观察到的毒性以外的生理效应表明，暴露于二氧化硅纳米颗粒后，可能存在肥胖或躯体和成骨发育缺陷的风险。此外，鉴于Wnt信号在肿瘤发生和癌症转移中的临床意义，我们的工作还首次在纳米材料和Wnt信号通路之间建立了分子联系，这为未经修饰的二氧化硅纳米颗粒在癌症和其他危重疾病的靶向治疗中的新应用打开了新的大门。
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.