Cocktail polyprodrug nanoparticles concurrently release cisplatin and peroxynitrite-generating nitric oxide in cisplatin-resistant cancers

•Cocktail polyprodrug of nitric oxide and cisplatin can reverse cisplatin resistance.•Highly cytotoxic peroxynitrite is specifically generated inside cancer cells.•Cocktail polyprodrug design is applicable for other diseases in precision medicine. Severe multidrug resistance has frequently compromised the therapeutic efficacy of one first-line chemotherapeutic drug cisplatin. Here, we report cocktail polyprodrug nanoparticles (CPNs) that can concurrently pump out nitric oxide (NO) and peroxynitrite (ONOO−) in response to reductive cytosolic milieu to overcome cisplatin-resistant cancers. Branched polyprodrug amphiphiles of cisplatin and nitric oxide (NO), P(DMA-co-PtMA-co-StNO), are facilely fabricated from one-pot copolymerization of cisplatin prodrug crosslinker monomer (PtMA), NO prodrug monomer (StNO), and hydrophilic monomer, N, N-dimethylacrylamide (DMA). The branched polyprodrug containing dual prodrugs can self-assemble into spherical CPNs in water. Upon cellular uptake by cancer cells, CPNs are degraded by reductive cytosolic milieu to concurrently release NO and cisplatin dual parent drugs at local sites. The released cisplatin can activate nicotinamide adenine dinucleotide phosphate oxidase (NOXs) to catalyze O2 into superoxide (O2−), which further reacts with in-situ released NO to produce highly reactive ONOO− that is more lethal than O2− or NO only. In vitro and in vivo analyses demonstrate that CPNs can efficiently overcome cisplatin resistance by current collaborative modalities. The rational design of cocktail polyprodrug provides a confined space to pump out NO and ONOO− efficiently, which has alluringprospect to reverse the cisplatin resistance for precision clinical cancer therapy.