A self-reinforcing nanoplatform for triple-synergistic therapy: NIR-triggered photothermal/gas/chemodynamic therapy of tumors.

Introduction: A major challenge in nanomedicine is developing multifunctional nanoplatforms capable of achieving synergistic cancer therapy. Methods: In the present study, we developed a CD44-targeted nanocomposite, named UiO-SNO@CuS/HA, for efficacy evaluation in combination therapy including photothermal therapy (PTT), nitric oxide (NO) gas therapy and chemodynamic therapy (CDT) The nanoplatform was produced through the preparation of UiO-66-SH metal-organic framework (MOF) followed by the post-synthetic nitrosation of S-thiols to give S-nitrosothiols (SNO) as the NO donor. Afterward, in situ growth of ultrasmall CuS nanoparticles on the MOF surface led to the eventual coating of the hybrids with hyaluronic acid (HA) for active tumor targeting. Results: Under 1064 nm laser irradiation, the CuS component mediated effective PTT with a photothermal conversion efficiency of 41.4%. The generated photothermal heat also leads to the release of a considerable amount of the gas NO (135 μM, pH 4.6) and promotes the release the ions Cu2 + in the acidic tumor microenvironment. The Cu2+ that was released was reduced to Cu+ by glutathione, achieving GSH depletion of around 80%. This not only triggered a Fenton-like reaction with H2O2 to produce reactive hydroxyl radicals (·OH) for CDT, but also stimulated further production of NO from SNO moieties, forming a self-propagating therapeutic cycle. The series of events led to an increase of 4.2 times generation of intracellular reactive oxygen species (ROS), severe mitochondrial dysfunction with a decrease of 85% in membrane potential, and finally 78.4% apoptosis was induced in HeLa cells. Discussion: The triple-combination therapy generated by UiO-SNO@CuS/HA was demonstrated to have much higher cancer cell killing efficacy in vitro than either single or dual therapies, and very good biocompatibility with normal cells. This study reports a rationally designed feedback-amplified nanosystem that enables potent and specific triple-synergistic tumor therapy, representing a practical strategy for advanced combinatorial cancer therapy.