Tumor microenvironment-responsive artesunate loaded Z-scheme heterostructures for synergistic photo-chemodynamic therapy of hypoxic tumor

Tumor microenvironment (TME) with the particular features of severe hypoxia, insufficient endogenous H 2 O 2 , and overexpression of glutathione (GSH) markedly reduced the antitumor efficacy of monotherapy. Herein, a TME-responsive multifunctional nanoplatform (Bi 2 S 3 @ [email protected] /Art NRs) was presented for synergistic photothermal therapy (PTT), chemodynamic therapy (CDT), and photodynamic therapy (PDT) to achieve better therapeutic outcomes. The Z-scheme heterostructured bismuth [email protected] nanorods (Bi 2 S 3 @Bi NRs) guaranteed excellent photothermal performance of the nanoplatform. Moreover, its ability to produce O 2 and reactive oxygen species (ROS) synchronously could relieve tumor hypoxia and improve PDT outcomes. The densely coated polydopamine/ammonium bicarbonate (PDA/ABC) and hyaluronic acid (HA) layers on the surface of the nanoplatform enhanced the cancer-targeting capacity and induced the acidic TME-triggered in situ “bomb-like” release of Art. The CDT treatment was achieved by activating the released Art through intracellular Fe 2+ ions in an H 2 O 2 -independent manner. Furthermore, decreasing the glutathione peroxidase 4 (GPX4) levels by Art could also increase the PDT efficiency of Bi 2 S 3 @Bi NRs. Owing to the synergistic effect, this nanoplatform displayed improved antitumor efficacy with minimal toxicity both in vitro and in vivo . Our design sheds light on the application of phototherapy combined with the traditional Chinese medicine monomer-artesunate in treating the hypoxic tumor.