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Efficient and biologically safe mode of cold atmospheric plasma jet (CAPJ) is crucial for the development of CAPJ-based anticancer therapy. In the experiment and numerical simulations, by changing the pulse duration of a positive-pulsed voltage, we found the optimal CAPJ mode with regular streamer propagation. CAPJ regimes with a maximum discharge current at a temperature T<42 C substantially suppressed the viability of cancer cells. To enhance cell killing, gold nanoparticles (NPs) were added to the cells before and after the CAPJ exposure. Combination of CAPJ, generated with positive pulsed voltage, and gold nanoparticles decreased viability of NCI-H23 epithelial-like lung adenocarcinoma, A549 lung adenocarcinoma, BrCCh4e-134 breast adenocarcinoma and uMel1 uveal melanoma cells. Polyethylene glycol-modified nanoparticles with attached fluorescent label were used to visualize the uptake of NPs. We demonstrated that NPs efficiently entered the cells when were added to the cells just before CAPJ exposure or up to two hours afterwards. The efficiency ofNPs penetration into cells positively correlated with the induced cytotoxic effect: it was maximal when NPs was added to cells right before or immediately after CAPJ exposure. Summarizing, the treatment with optimal CAPJ modes in combination with modified NPs, bearing the cancer-addressed molecules and therapeutics may be next strategy of strengthening the CAPJ-based antitumor approaches., Comment: 19 pages, 8 figures, submitted to Journal of Physics D: Applied Physics The research was funded by Russian Science Foundation grant number 22-49-08003. The research on uMel1 cells cultivation was funded by Russian Science Foundation grant number 23-14-00285