Selectively cuting off the nutrient supply and the metabolism pathways of cancer cells would be a promising approach to improve the efficiency of cancer treatment. Here, a cancer targeted cascade bioreactor (designated as mCGP) was constructed for synergistic starvation and photodynamic therapy (PDT) by embedding glucose oxidase (GOx) and catalase in the cancer cell membrane-camouflaged porphyrin metal-organic framework (MOF) of PCN-224 (PCN stands for porous coordination network). Due to biomimetic surface functionalization, the immune escape and homotypic targeting behaviors of mCGP would dramatically enhance its cancer targeting and retention abilities. Once internalized by cancer cells, mCGP was found to promote microenvironmental oxygenation by catalyzing the endogenous hydrogen peroxide (HO) to produce oxygen (O), which would subsequently accelerate the decomposition of intracellular glucose and enhance the production of cytotoxic singlet oxygen (O) under light irradiation. Consequently, mCGP displayed amplified synergistic therapeutic effects of long-term cancer starvation therapy and robust PDT, which would efficiently inhibit the cancer growth after a single administration. This cascade bioreactor would further facilitate the development of complementary modes for spatiotemporally controlled cancer treatment.

Chemodynamic therapy (CDT) can efficiently destroy tumor cells via Fenton reaction in the presence of H 2 O 2 and a robust catalyst. However, it has faced severe challenges including the limited amounts of H 2 O 2 and inefficiency of catalysts.Here, an adenosine triphosphate (ATP)-responsive autocatalytic Fenton nanosystem (GOx@ZIF@MPN), incorporated with glucose oxidase (GOx) in zeolitic imidazolate framework (ZIF) and then coated with metal polyphenol network (MPN), was designed and synthesized for tumor ablation with self-supplied H 2 O 2 and TA-mediated acceleration of Fe(III)/Fe(II) conversion. In the ATP-overexpressed tumor cells, the outer shell MPN of GOx@ZIF@MPN was degraded into Fe(III) and tannic acid (TA) and the internal GOx was exposed. Then, GOx reacted with the endogenous glucose to produce plenty of H 2 O 2 , and TA reduced Fe(III) to Fe(II), which is a much more vigorous catalyst for the Fenton reaction. Subsequently, self-produced H 2 O 2 was catalyzed by Fe(II) to generate highly toxic hydroxyl radical (•OH) and Fe(III). The produced Fe(III) with low catalytic activity was quickly reduced to reactive Fe(II) mediated by TA, forming an accelerated Fe(III)/Fe(II) conversion to guarantee efficient Fenton reaction-mediated CDT. This autocatalytic Fenton nanosystem might provide a good paradigm for effective tumor treatment.

Here, a Mn­(III)-sealed metal–organic framework (MOF) nanosystem based on coordination between Mn­(III) and porphyrin (TCPP) via a one-pot method was designed and constructed. Mn­(III), as a sealer, not only quenched TCPP-based fluorescence but also inhibited reactive oxygen species (ROS) generation, which made MOFs an “inert” theranostic nanoparticle. Interestingly, upon endocytosis by tumor cells, MOFs were disintegrated into Mn­(II) and free TCPP by intracellular glutathione (GSH) in tumor cells, owing to redox reaction between Mn­(III) and GSH. This disintegration would lead to consumption of antioxidant GSH and activated Mn­(II)-based magnetic resonance imaging (MRI) as well as TCPP-based fluorescent imaging. More importantly, such a GSH-regulated TCPP release could implement controllable ROS generation under irradiation, which avoided side effects (inflammation and damage of normal tissues). As a consequence, after unlocking by GSH, Mn­(III)-sealed MOFs could significantly improve the therapeutic efficiency of photodynamic therapy by combining controlled ROS generation and GSH depletion after precise dual tumor homing.

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Drug delivery systems (DDSs) with biocompatibility and precise drug delivery are eagerly needed to overcome the paradox in chemotherapy that high drug doses are required to compensate for the poor biodistribution of drugs with frequent dose-related side effects. In this work, we reported a metal-organic framework (MOF) based tumor targeting DDS developed by a one-pot, and organic solvent-free "green" post-synthetic surface modification procedure, starting from the nanoscale MOF MIL-101. Owing to the multifunctional surface coating, premature drug release from this DDS was prevented. Due to the pH responsive benzoic imine bond and the redox responsive disulfide bond at the modified surface, this DDS exhibited tumor acid environment enhanced cellular uptake and intracellular reducing environment triggered drug release. In vitro and in vivo results showed that DOX loaded into this DDS exhibited effective cancer cell inhibition with much reduced side effects.