Tuning cell behavior with nanoparticle shape

We investigated how the shape of polymeric vesicles, made by the exact same material, impacts the replication activity and metabolic state of both cancer and non-cancer cell types. First, we isolated discrete geometrical structures (spheres and tubes) from a heterogeneous sample using density-gradient centrifugation. Then, we characterized the cellular internalization and the kinetics of uptake of both types of polymersomes in different cell types (either cancer or non-cancer cells). We also investigated the cellular metabolic response as a function of the shape of the structures internalized and discovered that tubular vesicles induce a significant decrease in the replication activity of cancer cells compared to spherical vesicles. We related this effect to the significant up-regulation of the tumor suppressor genes p21 and p53 with a concomitant activation of caspase 3/7. Finally, we demonstrated that combining the intrinsic shape-dependent effects of tubes with the delivery of doxorubicin significantly increases the cytotoxicity of the system. Our results illustrate how the geometrical conformation of nanoparticles could impact cell behavior and how this could be tuned to create novel drug delivery systems tailored to specific biomedical application.

本研究针对同一材料制备的聚合物囊泡（polymeric vesicles）的形状对癌细胞与非癌细胞的增殖活性及代谢状态的影响展开了探究。首先，本研究通过密度梯度离心法，从异质性样本中分离得到两种离散几何结构：球形囊泡与管状囊泡。随后，本研究表征了两类聚合物囊泡在不同细胞系（癌细胞与非癌细胞）中的细胞内化过程与摄取动力学。此外，本研究还探究了细胞代谢响应随内化结构形状的关联规律，发现相较于球形囊泡，管状囊泡可显著降低癌细胞的增殖活性。本研究将该效应归因于抑癌基因p21与p53的显著上调，同时伴随半胱天冬酶caspase 3/7的激活。最后，本研究证实，将管状囊泡固有的形状依赖效应与阿霉素（doxorubicin）递送相结合，可显著提升该体系的细胞毒性。本研究结果阐明了纳米颗粒的几何构象如何影响细胞行为，并揭示了可通过调控该构象开发适配特定生物医学应用的新型药物递送系统。