A tumor-targeted multifunctional nanosystem with light-triggered NO generation for synergistic photodynamic/gas therapy

Photodynamic therapy (PDT) has emerged as a promising strategy for cancer treatment. Nevertheless, PDT alone still faces a considerable challenge in efficiently eliminating cancer cells, and combination with other therapeutic strategies can significantly improve anticancer efficacy. Herein, a multifunctional nanosystem (Ru-PArg-HA) composed of biocompatible and tumor-targeted hyaluronic acid (HA), a photosensitizer [Ru(phen)2(PIP-OCH3)]2+ (termed Ru, phen = 1,10-phenanthroline, PIP-OCH3 = 2-(4-methoxy phenyl)-1H-imidazo[4,5-f] [1,10] phenanthroline) and a NO donor poly-l-arginine (PArg), was fabricated via electrostatic interactions. Under 470 nm light irradiation, Ru-PArg-HA could not only catalyze 1,4-dihydronicotinamide adenine dinucleotide (NADH) oxidation to produce H2O2, but also could generate a large amount of reactive oxygen species (ROS, including 1O2 and O2−) for PDT therapy. The light-driven production of 1O2 and H2O2 could further convert PArg into nitric oxide (NO), enabling synergistic gas therapy. The experimental outcomes demonstrated that Ru-PArg-HA exhibited much enhanced anticancer activity compared to traditional mono-modal PDT. This finding provides new inspiration for the development of multifunctional nanosystems with efficient and targeted anticancer activity.