这项研究探讨了生物分子机制的基础上的抗肿瘤功效的混合纳米系统,由用转铁蛋白(Tf)官能化的银核@壳(Ag@MSNs)组成。采用SILAC蛋白质组学策略,我们在暴露于纳米系统后鉴定出超过150种失调的蛋白质.这些蛋白质在不同的细胞过程中发挥关键作用,包括线粒体裂变,钙稳态,内质网(ER)应激,氧化应激反应,迁移,入侵,蛋白质合成,RNA成熟,化学抗性,和细胞增殖。对关键发现的严格验证证实,纳米系统通过激活线粒体裂变来引发其抗肿瘤作用,导致钙稳态的破坏,如RT-qPCR和流式细胞术分析所证实。此外,ER应激的诱导通过ER应激标志物的蛋白质印迹得到验证。通过胞质和线粒体活性氧(ROS)的产生,进一步肯定了纳米系统的细胞毒性作用。最后,使用鸡胚模型的体内实验不仅证实了纳米系统的抗肿瘤能力,而且还证明了其在减少细胞增殖方面的功效。这些全面的发现证明了设计的Ag@MSNs-Tf纳米系统作为开创性化学治疗剂的潜力,阐明其多方面的机制和体内适用性。
This study delves into the biomolecular mechanisms underlying the antitumoral efficacy of a hybrid nanosystem, comprised of a silver core@shell (Ag@MSNs) functionalized with transferrin (Tf). Employing a
SILAC proteomics strategy, we identified over 150 de-regulated proteins following exposure to the nanosystem. These proteins play pivotal roles in diverse cellular processes, including mitochondrial fission, calcium homeostasis, endoplasmic reticulum (ER) stress, oxidative stress response, migration, invasion, protein synthesis, RNA maturation, chemoresistance, and cellular proliferation. Rigorous validation of key findings substantiates that the nanosystem elicits its antitumoral effects by activating mitochondrial fission, leading to disruptions in calcium homeostasis, as corroborated by RT-qPCR and flow cytometry analyses. Additionally, induction of ER stress was validated through western blotting of ER stress markers. The cytotoxic action of the nanosystem was further affirmed through the generation of cytosolic and mitochondrial reactive oxygen species (ROS). Finally, in vivo experiments using a chicken embryo model not only confirmed the antitumoral capacity of the nanosystem, but also demonstrated its efficacy in reducing cellular proliferation. These comprehensive findings endorse the potential of the designed Ag@MSNs-Tf nanosystem as a groundbreaking chemotherapeutic agent, shedding light on its multifaceted mechanisms and in vivo applicability.