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The conversion of endogenous H2O2 into toxic hydroxyl radical (•OH) via catalytic nanoparticles is explored for tumor therapy and received considerable success. The intrinsic characteristics of microenvironment in tumor cells, such as limited H2O2 and overexpressed glutathione (GSH), hinder the intracellular •OH accumulation and thus weaken therapeutic efficacy considerably. In this study, fine CaO2 nanoparticles with Cu–ferrocene molecules at the surface (CaO2/Cu–ferrocene) are successfully designed and synthesized. Under an acidic condition, the particles release Ca2+ ions and H2O2 in a rapid fashion, while they can remain stable in neutral. In addition, agitated production of •OH occurs following the Fenton reaction of H2O2 and ferrocene molecules, and GSH is consumed by Cu2+ ions to avoid the potential •OH consumption. More interestingly, in addition to the exogenous Ca2+ released by the particles, the enhanced •OH production facilitates intracellular calcium accumulation by regulating Ca2+ channels and pumps of tumor cells. It turns out that promoted •OH induction and intracellular calcium overload enable significant in vitro and in vivo antitumor phenomena., For the first time, fine CaO2 nanoparticles functionalized with Cu–ferrocene molecules, named as CaO2/Cu–ferrocene, are successfully constructed, enabling unique characteristics including hydroxyl radical (•OH) induction with self‐supplied H2O2, glutathione (GSH) depletion, and calcium overload within tumor cells. Considerable in vitro and in vivo anticancer properties are achieved for tumor‐specific therapy.

Drug transportation is impeded by various barriers in the hypoxic solid tumor, resulting in compromised anticancer efficacy. Herein, a solid lipid monostearin (MS)-coated CaO2/MnO2 nanocarrier was designed to optimize doxorubicin (DOX) transportation comprehensively for chemotherapy enhancement. The MS shell of nanoparticles could be destroyed selectively by highly-expressed lipase within cancer cells, exposing water-sensitive cores to release DOX and produce O2. After the cancer cell death, the core-exposed nanoparticles could be further liberated and continue to react with water in the tumor extracellular matrix (ECM) and thoroughly release O2 and DOX, which exhibited cytotoxicity to neighboring cells. Small DOX molecules could readily diffuse through ECM, in which the collagen deposition was decreased by O2-mediated hypoxia-inducible factor-1 inhibition, leading to synergistically improved drug penetration. Concurrently, DOX-efflux-associated P-glycoprotein was also inhibited by O2, prolonging drug retention in cancer cells. Overall, the DOX transporting processes from nanoparticles to deep tumor cells including drug release, penetration, and retention were optimized comprehensively, which significantly boosted antitumor benefits., Graphical abstract Synergistic drug penetration, sufficient drug release, and prolonged drug retention were concurrently realized by a smart O2-generating nanocarrier, contributing to comprehensively optimized drug transportation and thereby improved chemotherapy.Image 1

Combined chemo/chemodynamic therapy is a promising strategy to achieve an improved anticancer effect. However, the hypoxic microenvironment and limited amount of H2O2 in most solid tumors severely restrict the efficacy of this treatment. Herein, the construction of a nanocatalytic medicine, CaO2@DOX@ZIF‐67, via a bottom‐up approach is described. CaO2@DOX@ZIF‐67 simultaneously supplies O2 and H2O2 to achieve improved chemo/chemodynamic therapy. In the weakly acidic environment within tumors, CaO2@DOX@ZIF‐67 is broken down to rapidly release the Fenton‐like catalyst Co2+ and the chemotherapy drug doxorubicin (DOX). The unprotected CaO2 reacts with H2O to generate both O2 and H2O2. The generated O2 relieves the hypoxia in the tumor and further improve the efficacy of DOX. Meanwhile, the generated H2O2 reacts with Co2+ ions to produce highly toxic •OH through a Fenton‐like reaction, resulting in improved chemodynamic therapy., The hypoxic microenvironment and limited amount of H2O2 in most solid tumors severely restrict the efficacy of chemotherapy and chemodynamic therapy, respectively. Herein, a nanocatalytic medicine, CaO2@DOX@ZIF‐67, is synthesized via a bottom‐up approach. By virtue of simultaneously producing O2 and H2O2 under acidic conditions, the fabricated nanocatalytic medicine can eliminate hypoxic tumors via enhanced chemo/chemodynamic therapy.

The conversion of endogenous H2 O2 into toxic hydroxyl radical (• OH) via catalytic nanoparticles is explored for tumor therapy and received considerable success. The intrinsic characteristics of microenvironment in tumor cells, such as limited H2 O2 and overexpressed glutathione (GSH), hinder the intracellular • OH accumulation and thus weaken therapeutic efficacy considerably. In this study, fine CaO2 nanoparticles with Cu-ferrocene molecules at the surface (CaO2 /Cu-ferrocene) are successfully designed and synthesized. Under an acidic condition, the particles release Ca2+ ions and H2 O2 in a rapid fashion, while they can remain stable in neutral. In addition, agitated production of • OH occurs following the Fenton reaction of H2 O2 and ferrocene molecules, and GSH is consumed by Cu2+ ions to avoid the potential • OH consumption. More interestingly, in addition to the exogenous Ca2+ released by the particles, the enhanced • OH production facilitates intracellular calcium accumulation by regulating Ca2+ channels and pumps of tumor cells. It turns out that promoted • OH induction and intracellular calcium overload enable significant in vitro and in vivo antitumor phenomena.