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 2 -generation/O 2 -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 2 (H-MnO 2 ) nanoparticles, ICG/Met@H-MnO 2 @MPN-FA (IMMMF) was conveniently prepared through the formation of metal–phenolic networks (MPNs) between Fe 3+ 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 2+ and Fe 2+ for enhanced CDT, and ICG for SDT. Furthermore, Met was continuously released to reduce O 2 consumption for enhanced SDT. More importantly, IMMMF catalyzed the endogenous H 2 O 2 into O 2 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.
Reprogramming of tumor associated macrophages (TAMs) from M2 to M1 phenotype is becoming a feasible strategy for tumor immunotherapy, however, its efficacy is potentially constrained by the acellular components of immunosuppressive tumor microenvironment (TME). Herein, hollow MnO 2 (HMnO 2 ) nanoparticles were loaded with autophagy inhibitor chloroquine (CQ), carried both lactate oxidase (LOX) and glucose oxidase (GOX) on their surface, and further were camouflaged with tumor cell membrane, forming the final mCMLG nanoparticles for TME immunostimulation. After intravenous injection, mCMLG nanoparticles effectively accumulated in the tumor area and were taken up by tumor cells. Under the acidic conditions, MnO 2 reacted with endogenous hydrogen peroxide (H 2 O 2 ) to generate O 2 and Mn 2+ , resulting in the exposure of LOX and GOX as well as the release of CQ. The exposed enzymes reduced the level of lactate (a predominant acellular component), alleviating the inhibition on TAM reprogramming; hydroxyl radical (·OH) generated by Fenton-like reaction of Mn 2+ could directly promote this reprogramming, thus effectively facilitating the reprogramming of TME from immunosuppressive to immunostimulatory. Moreover, ·OH also induced chemodynamic therapy (CDT) effect against tumor cells, which was further amplified by CQ. This study corroborates that mCMLG nanoparticles can effectively inhibit tumor growth through the enhanced immunotherapy and CDT.
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