Cationic colloidal gold nanorods (GNRs) have a great potential as a theranostic tool for diverse medical applications. GNRs' properties such as cellular internalization and stability are determined by physicochemical characteristics of their surface coating. GNRs modified by (16-mercaptohexadecyl)trimethylammonium bromide (MTAB), MTABGNRs, show excellent cellular uptake. Despite their promise for biomedicine, however, relatively little is known about the cellular pathways that facilitate the uptake of GNRs, their subcellular fate and intracellular persistence. Here we studied the mechanism of cellular internalization and long-term fate of GNRs coated with MTAB, for which the synthesis was optimized to give higher yield, in various human cell types including normal diploid versus cancerous, and dividing versus nondividing (senescent) cells. The process of MTABGNRs internalization into their final destination in lysosomes proceeds in two steps: (1) fast passive adhesion to cell membrane mediated by sulfated proteoglycans occurring within minutes and (2) slower active transmembrane and intracellular transport of individual nanorods via clathrin-mediated endocytosis and of aggregated nanorods via macropinocytosis. The expression of sulfated proteoglycans was the major factor determining the extent of uptake by the respective cell types. Upon uptake into proliferating cells, MTABGNRs were diluted equally and relatively rapidly into daughter cells; however, in nondividing/senescent cells the loss of MTABGNRs was gradual and very modest, attributable mainly to exocytosis. Exocytosed MTABGNRs can again be internalized. These findings broaden our knowledge about cellular uptake of gold nanorods, a crucial prerequisite for future successful engineering of nanoparticles for biomedical applications such as photothermal cancer therapy or elimination of senescent cells as part of the emerging rejuvenation approach.

Department of Chemistry Faculty of Science University of Hradec Kralove 500 03 Hradec Kralove Czech Republic

Department of Chemistry Faculty of Science University of Hradec Kralove 500 03 Hradec Kralove Czech Republic Biomedical Research Center University Hospital CZ 500 05 Hradec Kralove Czech Republic

Department of Genome Integrity Institute of Molecular Genetics of the CAS v v i CZ 142 20 Prague 4 Czech Republic

Department of Genome Integrity Institute of Molecular Genetics of the CAS v v i CZ 142 20 Prague 4 Czech Republic Department of Physical Electronics Faculty of Nuclear Sciences and Physical Engineering Czech Technical University Prague CZ 115 19 Prague 1 Czech Republic

Department of Genome Integrity Institute of Molecular Genetics of the CAS v v i CZ 142 20 Prague 4 Czech Republic Genome Integrity Unit Danish Cancer Society Research Center DK 2100 Copenhagen Denmark Department of Medical Biochemistry and Biophysics Science For Life Laboratory Division of Translational Medicine and Chemical Biology Karolinska Institute 17121 Solna Sweden

Laboratory of Molecular Structure Characterization Institute of Microbiology of the CAS v v i CZ 142 20 Prague 4 Czech Republic

Laboratory of Mutagenesis and Carcinogenesis Cancer Research Institute BMC Slovak Academy of Sciences 945 05 Bratislava Slovakia

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