Chemodynamic therapy (CDT) is an emerging therapy method that kills cancer cells by converting intracellular hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals (•OH). To overcome the current limitations of the insufficient endogenous H2O2 and the high concentration of glutathione (GSH) in tumor cells, an intelligent nanocatalytic theranostics (denoted as PGC‐DOX) that possesses both H2O2 self‐supply and GSH‐elimination properties for efficient cancer therapy is presented. This nanoplatform is constructed by a facile one‐step biomineralization method using poly(ethylene glycol)‐modified glucose oxidase (GOx) as a template to form biodegradable copper‐doped calcium phosphate nanoparticles, followed by the loading of doxorubicin (DOX). As an enzyme catalyst, GOx can effectively catalyze intracellular glucose to generate H2O2, which not only starves the tumor cells, but also supplies H2O2 for subsequent Fenton‐like reaction. Meanwhile, the redox reaction between the released Cu2+ ions and intracellular GSH will induce GSH depletion and reduce Cu2+ to Fenton agent Cu+ ions, and then trigger the H2O2 to generate •OH by a Cu+‐mediated Fenton‐like reaction, resulting in enhanced CDT efficacy. The integration of GOx‐mediated starvation therapy, H2O2 self‐supply and GSH‐elimination enhanced CDT, and DOX‐induced chemotherapy, endow the PGC‐DOX with effective tumor growth inhibition with minimal side effects in vivo.

Photodynamic therapy (PDT) has aroused great research interest in recent years owing to its high spatiotemporal selectivity, minimal invasiveness, and low systemic toxicity. However, due to the hypoxic nature characteristic of many solid tumors, PDT is frequently limited in therapeutic effect. Moreover, the consumption of O2 during PDT may further aggravate the tumor hypoxic condition, which promotes tumor proliferation, metastasis, and invasion resulting in poor prognosis of treatment. Therefore, numerous efforts have been made to increase the O2 content in tumor with the goal of enhancing PDT efficacy. Herein, these strategies developed in past decade are comprehensively reviewed to alleviate tumor hypoxia, including 1) delivering exogenous O2 to tumor directly, 2) generating O2 in situ, 3) reducing tumor cellular O2 consumption by inhibiting respiration, 4) regulating the TME, (e.g., normalizing tumor vasculature or disrupting tumor extracellular matrix), and 5) inhibiting the hypoxia‐inducible factor 1 (HIF‐1) signaling pathway to relieve tumor hypoxia. Additionally, the O2‐independent Type‐I PDT is also discussed as an alternative strategy. By reviewing recent progress, it is hoped that this review will provide innovative perspectives in new nanomaterials designed to combat hypoxia and avoid the associated limitation of PDT.

Photodynamic therapy (PDT) is exploited as a promising strategy for cancer treatment. However, the hypoxic solid tumor and the lack of tumor-specific photosensitizer administration hinder the further application of oxygen (O 2)-dependent PDT. In this study, a biodegradable and O 2 self-supplying nanoplatform for tumor microenvironment (TME)-specific activatable cascade catalytic reactions-augmented PDT is reported. The nanoplatform (named GMCD) is constructed by coloading catalase (CAT) and sinoporphyrin sodium (DVDMS) in the manganese (Mn)-doped calcium phosphate mineralized glucose oxidase (GOx) nanoparticles. The GMCD can effectively accumulate in tumor sites to achieve an "off to on" fluorescence transduction and a TME-activatable magnetic resonance imaging. After internalization into cancer cells, the endogenous hydrogen peroxide (H 2 O 2) can be catalyzed to generate O 2 by CAT, which not only promotes GOx catalytic reaction to consume more intratumoral glucose, but also alleviates tumor hypoxia and enhances the production of cytotoxic singlet oxygen from light-triggered DVDMS. Moreover, the H 2 O 2 generated by GOx-catalysis can be converted into highly toxic hydroxyl radicals by Mn 2+-mediated Fenton-like reaction, further amplifying the oxidative damage of cancer cells. As a result, GMCD displays superior therapeutic effects on 4T1-tumor bearing mice by a long term cascade catalytic reactions augmented PDT.

To design a clinically translatable nanomedicine for photodynamic theranostics, the ingredients should be carefully considered. A high content of nanocarriers may cause extra toxicity in metabolism, and multiple theranostic agents would complicate the preparation process. These issues would be of less concern if the nanocarrier itself has most of the theranostic functions. In this work, a poly(ethylene glycol)‐boron dipyrromethene amphiphile (PEG‐F54‐BODIPY) with 54 fluorine‐19 (19F) is synthesized and employed to emulsify perfluorohexane (PFH) into a theranostic nanoemulsion (PFH@PEG‐F54‐BODIPY). The as‐prepared PFH@PEG‐F54‐BODIPY can perform architecture‐dependent fluorescence/photoacoustic/19F magnetic resonance multimodal imaging, providing more information about the in vivo structure evolution of nanomedicine. Importantly, this nanoemulsion significantly enhances the therapeutic effect of BODIPY through both the high oxygen dissolving capability and less self‐quenching of BODIPY molecules. More interestingly, PFH@PEG‐F54‐BODIPY shows high level of tumor accumulation and long tumor retention time, allowing a repeated light irradiation after a single‐dose intravenous injection. The “all‐in‐one” photodynamic theranostic nanoemulsion has simple composition, remarkable theranostic efficacy, and novel treatment pattern, and thus presents an intriguing avenue to developing clinically translatable theranostic agents.

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