Intracellular Mechanistic Understanding of 2D MoS2 Nanosheets for Anti-Exocytosis-Enhanced Synergistic Cancer Therapy

• Published in: ACS nano 2018-03, Vol.12 (3), p.2922-2938
• Main Authors: Zhu, Xianbing, Ji, Xiaoyuan, Kong, Na, Chen, Yunhan, Mahmoudi, Morteza, Xu, Xiaoding, Ding, Li, Tao, Wei, Cai, Ting, Li, Yujing, Gan, Tian, Barrett, Austin, Bharwani, Zameer, Chen, Hongbo, Farokhzad, Omid C
• Format: Article
• Language: English
• ISSN: 1936-0851; 1936-086X; 1936-086X
• DOI: 10.1021/acsnano.8b00516

Emerging two-dimensional (2D) nanomaterials, such as transition-metal dichalcogenide (TMD) nanosheets (NSs), have shown tremendous potential for use in a wide variety of fields including cancer nanomedicine. The interaction of nanomaterials with biosystems is of critical importance for their safe and efficient application. However, a cellular-level understanding of the nano-bio interactions of these emerging 2D nanomaterials (i.e., intracellular mechanisms) remains elusive. Here we chose molybdenum disulfide (MoS2) NSs as representative 2D nanomaterials to gain a better understanding of their intracellular mechanisms of action in cancer cells, which play a significant role in both their fate and efficacy. MoS2 NSs were found to be internalized through three pathways: clathrin → early endosomes → lysosomes, caveolae → early endosomes → lysosomes, and macropinocytosis → late endosomes → lysosomes. We also observed autophagy-mediated accumulation in the lysosomes and exocytosis-induced efflux of MoS2 NSs. Based on these findings, we developed a strategy to achieve effective and synergistic in vivo cancer therapy with MoS2 NSs loaded with low doses of drug through inhibiting exocytosis pathway-induced loss. To the best of our knowledge, this is the first systematic experimental report on the nano-bio interaction of 2D nanomaterials in cells and their application for anti-exocytosis-enhanced synergistic cancer therapy.