From perinuclear to intranuclear localization: A cell-penetrating peptide modification strategy to modulate cancer cell migration under mild laser irradiation and improve photothermal therapeutic performance.

Tumor metastasis is a key cause that leads to the failure of cancer treatment. Inhibition of metastasis, rather than the simple removal of the primary tumor, is critical to the survival improvement. Here, we report a cell-penetrating peptide-modification strategy to realize substantial perinuclear accumulation and subsequent near-infrared (NIR) laser-triggered nuclear entry of palladium nanosheets (Pd NSs) for inhibition of cancer cell metastasis and photothermal cancer therapy. Specifically, it was found that the cell-penetrating peptide TAT-modified Pd NSs (abbreviated as Pd-TAT) mainly accumulated in the perinuclear region and showed the enhanced endocytosis and reduced efflux compared with the counterpart without TAT modification. On the one hand, Pd-TAT could inhibit cell migration and invasion. It was proposed that Pd-TAT located in the perinuclear region could promote the overexpression of lamin A/C proteins (related with nuclear stiffness) and increase the mechanical stiffness of the nucleus. More importantly, the introduction of NIR laser irradiation with a laser density of 0.3 W/cm2 (below the permitted value 0.329 W/cm2 for skin exposure) significantly enhanced the inhibitory effect of Pd-TAT on cancer cell migration, which might be due to the increased nuclear stiffness caused by the enhanced nuclear entry of Pd-TAT under the effect of mild laser-induced local hyperthermia in the perinuclear region. On the other hand, the increased nuclear entry of Pd-TAT under NIR laser irradiation greatly enhanced their photothermal therapeutic efficacy due to the susceptibility of the nucleus to hyperthermia. Taken together, the Pd-TAT-based and laser-promoted perinuclear-to-intranuclear localization strategy allows us to not only destroy the primary tumor more effectively, but also inhibit cancer metastasis more persistently.