Abstract
Multiple biological barriers and tumor metastasis severely impede the tumor therapy. To address these adversities, an acid-activated poly (ethylene glycol)-poly-l-lysine-2,3-dimethylmaleic anhydride/poly (ε-caprolactone)-poly(l-arginine)/β-lapachone nanoparticles (mPEG-PLL-DMA/PCL-P(L-arg)/β-Lap, PLM/PPA/β-Lap NPs) were constructed with charge-reversal and size-reduction for β-Lap delivery with a cascade reaction of reactive oxygen species (ROS) and nitric oxide (NO) production. The nanosystem exhibited highly penetrable, superior cellular uptake and desirable endo-lysosomal escape thanks to size-reduction, charge-reversal and proton sponge, respectively. The vast bulk of ROS, which rapidly generated from β-Lap under high concentration quinone oxidoreductase 1 (NQO1), catalyzed guanidine groups to produce NO and generated highly toxic peroxynitrite (ONOO-). ONOO- would activate pro-matrix metalloproteinases (pro-MMPs) to generate MMPs, degrade the dense extracellular matrix (ECM) to augment the penetration capability, and aggravate DNA damage. NO and ONOO- influenced mitochondrial function by decreasing mitochondrial membrane potential and prevented the production of adenosine triphosphate (ATP), which inhibited the ATP-dependent tumor-derived microvesicles (TMVs) and restrained tumor metastasis. NO was defined as an epithelial mesenchymal transition (EMT) inhibitor to restrain tumor metastasis. All consequences demonstrated that PLM/PPA/β-lap NPs exhibited efficient penetration capability, outstanding anti-metastasis activity and favorable antitumor efficacy. Those novel acid-activated NPs are intended to provide further inspiration for multifunctional NO gas therapy.