Fig. 1: Schematic illustration of NMPNs-mediated concurrent DNA platination and oxidative cleavage to overcome Pt resistance of cancer.
The outermost mPEG5K-AC-CA of NMPNs can be selectively dissociated in tumour acidic microenvironment due to the hydrolysis of the β-thiopropionate group, thus exposing TAT peptides to promote the endocytosis, endosomal escape, and nuclear transportation. NMPNs can efficiently release Pt ions to induce Pt-DNA adducts in the nucleus of cisplatin-resistant tumour cells. Meanwhile, due to the highly active OXD and POD-like activities, NMPNs generate in situ reactive oxygen species (ROS) to induce the oxidative DNA cleavage near the Pt-DNA binding sites, which prohibits further DNA bending and thus destroying the DNA conformation required for NER. Intriguingly, the recruitment of NER effectors (XPA and XPF) to the DNA lesion sites has been disrupted. Consequently, the NMPNs induced and tailored Pt-DNA adducts can efficiently accumulate in the tumour cells without NER-mediated repairing, thus inducing the apoptosis of cisplatin-resistant tumour cells, as well as exerting a potent anti-tumour effect in vivo.
