Cisplatin is widely used in the chemoradiotherapy (CRT) of cervical cancers. However, despite the severe systemic side effects, the therapeutic efficacy of cisplatin is often compromised by the development of drug resistance, which is closely related to the elevated intracellular thiol-containing species (especially glutathione (GSH)) and the adenosine triphosphate (ATP)-dependent glutathione S-conjugate pumps. The construction of a safe and redox-sensitive nano-sensitizer with high disulfide density and high Pt(IV) prodrug loading capacity (up to 16.50% N and even higher), as described herein, is a promising way to overcome the cisplatin resistance and enhance the CRT efficacy. The optimized nanoparticles (NPs) (referred to as (CV5)-C-ss) with moderate N loading (7.62% N) and median size (c.a. 40 nm) was screened out and used for further biological evaluation. Compared with free cisplatin, more drugs could be transported and released inside the cisplatin resistant cells (Hela-CDDP) by (CV5)-C-ss NPs. With the synergistic effect of GSH scavenging and mitochondrial damage, (CV5)-C-ss NPs can easily reverse the cisplatin resistance. Moreover, the higher nucleus DNA binding N content of (CV5)-C-ss NPs not only caused the DNA damage and apoptosis of Hela-CDDP cells but also sensitized these cells to X-Ray radiation. The in vivo safety and efficacy results showed that (CV5)-C-ss NPs effectively accumulated inside tumor and inhibited the growth of cisplatin resistant xenograft models while alleviating the serious side effect associated with cisplatin (the maximum tolerated cisplatin equivalent of single injection is higher than 20 mg/kg body weight). The intervention of exogenous radiation further improved the anticancer efficacy of (CV5)-C-ss NPs and caused the shrinkage of tumor volume, thus making this safe and facile nano-sensitizer a promising route for the neoadjuvant CRT of cervical cancers.