Tumor-Specific ONOO– Nanogenerator for Improved Drug Delivery and Enhanced Chemotherapy of Tumor

Multiple biological barriers in solid tumors severely restrict the penetration of nanomedicines, which is a main cause for therapeutic failure in traditional tumor treatment. Here, a tumor-specific nanogenerator of peroxynitrite (ONOO-), prepared by loading cisplatin and sodium nitroprusside into poly(d,l-lactide-co-glycolide) polymersomes, was designed to improve drug delivery and enhance tumor chemotherapy. After a cascade of nicotinamide adenine dinucleotide phosphate oxidases catalysis and glutathione reduction, the nanogenerator, namely, PMCS, could selectively induce the generation of ONOO- in tumor. The generated ONOO- could not only strengthen vascular permeability significantly but also improve the accumulation and penetration of PMCS in tumor by activating matrix metalloproteinases-mediated degradation of extracellular matrix. Along with endocytosis, PMCS released cisplatin to induce tumor cell apoptosis. Moreover, free cisplatin liberated from dead cells infected neighboring tumor cells quickly via ONOO--mediated up-regulated copper transporter 1, further amplifying chemotherapeutic efficacy. This study advances ONOO- as a potent modality to address the main issues of therapeutic delivery, including but not limited to chemotherapy.