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Treatment resistance of the tumors to photodynamic therapy (PDT) owing to O2 deficiency largely compromised the therapeutic efficacy, which could be addressed via modulating oxygen levels by using O2 self-enriched nanosystems. Here, we report on augmenting the O2-evolving strategy based on a biomimetic, catalytic nanovehicle (named as N/P@MCC), constructed by the catalase-immobilized hollow mesoporous nanospheres by enveloping a cancer cell membrane (CCM), which acts as an efficient nanocontainer to accommodate nitrogen-doped graphene quantum dots (N-GQDs) and protoporphyrin IX (PpIX). Inheriting the virtues of biomimetic CCM cloaking, the CCM-derived shell conferred N/P@MCC nanovehicles with highly specific self-recognition and homotypic targeting toward cancerous cells, ensuring tumor-specific accumulation and superior circulation durations. N-GQDs, for the first time, have been evidenced as a new dual-functional nanoagents with PTT and PDT capacities, enabling the generation of 1O2 for PDT and inducing local low-temperature hyperthermia for thermally ablating cancer cells and infrared thermal imaging (IRT). Leveraging the intrinsic catalytic features of catalase, such N/P@MCC nanovehicles effectively scavenged the excessive H2O2 to sustainably evolve oxygen for a synchronous O2 self-supply and hypoxia alleviation, with an additional benefit because the resulting O2 bubbles could function as an echo amplifier, leading to the sufficient echogenic reflectivity for ultrasound imaging. Concurrently, the elevated O2 reacted with N-GQDs and PpIX to elicit a maximally increased 1O2 output for augmented PDT. Significantly, the ultrasound imaging coupled with fluorescence imaging, IRT, performs a tumor-modulated trimodal bioimaging effect. Overall, this offers a paradigm to rationally explore O2 self-supply strategies focused on versatile nanotheranostics for hypoxic tumor elimination.

The current reported photosensitizers generally show a decreased reactive oxygen species (ROS) generation property under hypoxia conditions, which is the main reason for the clinical failure of photodynamic therapy (PDT) in treatment of solid tumors. Herein, for the first time, hypoxia-induced photogenic radicals by eosin Y (Eos) were reported for efficient phototherapy of hypoxic tumors. More importantly, Eos shows a higher ROS and radical production efficiency under hypoxia conditions than under normoxia conditions. The photogenic radicals were captured by electron paramagnetic resonance and further verified by ROS and radical probe. Introducing CoCl

MicroRNAs (miRNAs) are involved in the essential progresses of many diseases and have emerged as therapeutic and diagnostic biomarkers. The combination of miRNA aberrant expression and tumor microenvironment (TME) features holds great potential for precise tumor imaging diagnosis but has been minimally explored. Herein, we rationally design a DNA@Cu-MOF nanosystem containing copper metal-organic frameworks (Cu-MOF) and a DNAzyme-assisted signal amplification procedure for deregulated miRNA-related hypoxic tumor diagnosis. The nanoprobes comprising a signal strand block Cu-specific DNAzyme precursor and a substrate strand are assembled on the surface of the hypoxia-responsive Cu-MOF. Under TME characterized by hypoxia, the DNA@Cu-MOF nanosystem disassociates and accomplishes the release of abundant Cu2+, DNAzyme precursor, and substrate strand. Target aberrant miRNA displaces the signal strand to recover one fluorescence signal for detection. Importantly, it activates the Cu-specific DNAzyme amplification, which produces miRNA aberrant expression-dependent fluorescence signal for hypoxic tumor diagnosis. Both in vitro and in vivo experiments validate its good performance for tumor cell diagnosis. The hypoxia-driven and miRNA-binding-induced self-powered and temporal-spatial fluorescence imaging nanosystem not only provides a great tool for aberrant miRNA-related hypoxic tumor diagnosis but also is readily applied for the control and modulation of biological functions.

Reports on the comprehensive factors for design considerations of hypoxia-activated prodrugs (HAPs) are rare. We introduced a new model system composed of a series of highly water-soluble HAPs, providing a platform to comprehensively understand the interaction between HAPs and hypoxic biosystems. Specifically, four kinds of new HAPs were designed and synthesized, containing the same biologically active moiety but masked by different bioreductive groups. Our results demonstrated that the activity of the prodrugs was strongly dependent on not only the molecular structure but also the hypoxic tumor microenvironment. We found the presence of a direct linear relationship between cytotoxicity of the HAPs and the reduction potential of whole molecule/oxygen concentration/reductase expression. Moreover, limited blood vasculature in hypoxic regions was also a critical barrier for effective activation of the HAPs. This study offers a comprehensive insight into understanding the design factors required for HAPs.

Photodynamic therapy (PDT) still faces a key challenge associated with its oxygen-dependent property, which limits its therapeutic efficiency against hypoxic tumor. To address the problem, covalent...

Free radicals have emerged as new-type and promising candidates for hypoxic tumor treatment, and further study of their therapeutic mechanism by real-time imaging is of great importance to explore their biomedical applications. Herein, we present a smart free-radical generator AuNC-V057-TPP for hypoxic tumor therapy; the AuNC-V057-TPP not only exhibits good therapeutic effect under both hypoxic and normoxic conditions but also can monitor the release of free radicals in real-time both in vitro and in vivo. What is more, with the mitochondria-targeting ability, the AuNC-V057-TPP is demonstrated with improved antitumor efficacy through enhanced free radical level in mitochondria, which leads to mitochondrial membrane damage and ATP production reduction and finally induces cancer cell apoptosis.

Metal–organic frameworks (MOFs) have been used for photodynamic therapy (PDT) of cancers by integrating photosensitizers, which cause cytotoxic effects on cancer cells by converting tumor oxygen into reactive singlet oxygen (1O2). However, the PDT efficiency of MOFs is severely limited by tumor hypoxia. Herein, by decorating platinum nanozymes on photosensitizer integrated MOFs, we report a simple yet versatile strategy for enhanced PDT. The platinum nanoparticles homogeneously immobilized on MOFs possess high stability and catalase-like activity. Thus, our nanoplatform can facilitate the formation of 1O2 in hypoxic tumor site via H2O2-activated evolvement of O2, which can cause more serious damage to cancer cells. Our finding highlights that the composites of nanozymes and MOFs have the potential to serve as efficient agents for cancer therapy, which will open an avenue of nanozymes and MOFs toward biological applications.