NIR/US-responsive injectable hyaluronic acid-based nickel sulfide hydrogel as a smart platform for synergistic antitumor therapy

Breast cancer is one of the most prevalent malignant tumors worldwide and a leading cause of cancer-related mortality, underscoring the urgent need for innovative therapeutic strategies. In this study, we developed an injectable hydrogel-based system, in which polyvinylpyrrolidone (PVP)-modified NiS 2-x @PVP nanospheres were incorporated with metformin hydrochloride (MH) and dispersed in a hyaluronic acid (HA) hydrogel matrix to form the NiS 2-x @PVP@HA tumor treatment platform. This system exhibits excellent photothermal performance under near-infrared (NIR) light irradiation and can be employed for tumor photothermal therapy (PTT). The Ni 2+ released from the degradation of NiS 2-x @PVP nanospheres can catalyze the decomposition of endogenous hydrogen peroxide in tumor cells, thereby generating toxic hydroxyl radicals for chemodynamic therapy (CDT). By altering the HA concentration, the internal pore structure, mechanical properties, drug release behavior, and swelling capacity of the hydrogel can be modulated. The loaded antitumor drug MH further enhances the therapeutic efficacy. Under NIR and ultrasound stimulation, this platform enables controlled drug release. In vitro and in vivo experiments have demonstrated that the NiS 2-x @PVP@HA hydrogel achieves the synergistic treatment of PTT/CDT/chemotherapy for tumor tissues. Kyoto Encyclopedia of Genes and Genomes pathway analysis suggested that activation of the MAPK signaling pathway was a key mechanism underlying tumor cell death. This work presents a rational design strategy that addresses the related challenges in breast cancer and promotes precise cancer therapy.