A nanodrug loading indocyanine green and metformin dually alleviating tumor hypoxia for enhanced chemodynamic/sonodynamic therapy.

As an emerging therapeutic method, the application of sonodynamic therapy (SDT) is hindered by its intrinsic unsatisfactory efficiency, the tumor hypoxia and low tumor specificity. Here, we reported the design of a tumor-targeting multifunctional nanodrug for O-generation/O-economization dually enhanced SDT/chemodynamic therapy (CDT) combination therapy. After the co-encapsulation of sonosensitizer indocyanine green (ICG) and oxidative phosphorylation inhibitor metformin (Met) into hollow MnO (H-MnO) nanoparticles, ICG/Met@H-MnO@MPN-FA (IMMMF) was conveniently prepared through the formation of metal-phenolic networks (MPNs) between Fe and folic acid (FA) immobilized tannic acid (TA, TA-FA) onto its surface. In vitro experiments indicated its selective uptake by 4T1 cells via the specific folate receptors-FA interactions. Responding to glutathione (GSH) and the acidic environment, the decomposition of IMMMF led to the release of Mn and Fe for enhanced CDT, and ICG for SDT. Furthermore, Met was continuously released to reduce O consumption for enhanced SDT. More importantly, IMMMF catalyzed the endogenous HO into O for further enhanced SDT. Expectedly, both in vitro and in vivo antitumor assays confirmed its satisfactory therapeutic efficiency via CDT/SDT synergistic therapy. Hence, this intelligent sonocatalytic nanoagent emerges as a promising candidate for CDT-enhanced SDT, which also provides a novel strategy for dually alleviating tumor hypoxia with better therapy.