摘要：Cancer stem cells(CSCs)are the driving force for sustainable tumor growth and metastasis and responsible for drug resistance and cancer relapse.Nanoparticle-based drug delivery has been demonstrated to be effective in combating tumor growth.However,it has been challenging to selectively eliminate CSCs due to the lack of a general signature for a spectrum of cancers.It is known that CSCs from various types of cancer show lower stiffness compared to non-CSCs.It remains unclear whether low stiffness in CSCs influences cellular uptake in nanoparticle-based drug delivery and thus the chemotherapy efficacy.Graphene quantum dot(GQD)is emerging as a promising carrier material in delivering anti-cancer drugs.We found that breast CSCs were softer than conventional cancer cells,which were further softer compared to healthy breast tissue cells.Importantly,soft CSCs uptook more GQD than conventional cancer cells,while stiff breast cancer cells with relatively low stiffness uptook more GQD than healthy breast cells.Softening cells by pharmacologically inhibiting actomyosin activity using either siRNA or actomyosin inhibitors significantly enhanced the cellular uptake of GQD in breast cancer cells but not CSCs,while stiffening cells by activating actomyosin using CA-MLCK/ROCK or actomyosin activators considerably suppressed the nanoparticle uptake in both cancer cells and CSCs.GQD could specifically target CSC because of low cell stiffness of CSC in breast cancer cell line MCF-7 and MDA-MB-231.Further regulating cell stiffness reflected that decreasing breast cancer cell stiffness by inhibiting actomyosin activity using blebbistatin could promote GQD uptake.Vice versa,stiffening cancer cell by activating actomyosin decreased GQD uptake.The attachment of anti-cancer drug doxorubicin did not alter the trend of GQD uptake in neither soften nor stiffen cancer cells.Actomyosin activity regulates cellular uptake ofGQD might through clathrin and caveolin-mediated endocytosis.Cancer cells are softer than normal cells from the same orga
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