Fig. 4. Augmented synthetic lethality for Pt by co-targeting XPA and MK2 in vivo.

a Schematic of dual-targeting peptide-based nanoplexes. b MK2 and XPA knockdown efficiency of nanoplex–siMK2/siXPA compared to lipofectamine RNAiMax–siMK2/siXPA measured by Western blotting for MK2 and XPA. Data representative of two independent experiments. c Representative bioluminescence images before and after indicated siRNA and cisplatin treatment on days 22, 29, 36, and 43. d Quantification of lung bioluminescence at 43 days after tumor implantation (n = 3 animals were used for each condition; only two mice remained alive in the nanoplex–siControl + cisplatin at day 43, and they died by day 50). Error bars represent mean ± SEM. e Representative H&E and Ki67 lung staining at the end of three rounds of the indicated treatments. Three animals were used for each condition. f Kaplan–Meier survival analysis of tumor-bearing mice treated with the indicated nanoplex–siRNA in combination with cisplatin treatment (nanoplex–siControl + cisplatin n = 6 animals, nanoplex–siMK2 + cisplatin n = 3 animals, nanoplex–siXPA + cisplatin n = 5 animals, and nanoplex–siMK2/siXPA + cisplatin n = 5 animals. *p ≤ 0.05 and **p ≤ 0.01 calculated using the log-rank test). g Model illustrating crosstalk between the MK2 signaling pathway and nucleotide excision repair in p53-defective cells. Co-targeting these pathways in established tumors prolongs spontaneous survival and potently enhances the antitumor response to cisplatin treatment.