Radiotherapy is a common cancer treatment approach in clinical practice, yet its efficacy has been restricted by tumor hypoxia. Nanomaterials‐mediated systemic delivery of glucose oxidase (GOx) and catalase (CAT) or CAT‐like nanoenzymes holds the potential to enhance tumor oxygenation. However, they face the challenge of intermediate (hydrogen peroxide [H2O2]) escape during systemic circulation if the enzyme pair is not closely placed to largely decompose H2O2, leading to oxidative stress on normal tissues. In the present study, a oxygen‐generating nanocascade, n(GOx‐CAT)C7A, constructed by strategically placing an enzymatic cascade (GOx and CAT) within a polymeric coating rich in hexamethyleneimine (C7A) moieties, is reported. During blood circulation, C7A remains predominantly non‐protonated , achieving prolonged blood circulation due to its low‐fouling surface. Once n(GOx‐CAT)C7A reaches the tumor site, the acidic tumor microenvironment (TME) induces protonation of C7A moieties, resulting in a positively charged surface for enhanced tumor transcytosis. Moreover, GOx and CAT are covalently conjugated into close spatial proximity (<10 nm) for effective H2O2 elimination. As demonstrated by the in vivo results, n(GOx‐CAT)C7A achieves effective tumor retention and oxygenation, potent radiosensitization and antitumor effects. Such a dual‐enzyme nanocascade for smart O2 delivery holds great potential for enhancing the hypoxia‐compromised cancer therapies.
Regulation of gene expression is conducive to understanding the physiological roles of specific genes and provides therapeutic potentials, which however still remains a great challenge. Nonviral carriers have some advantages for gene delivery compared to traditional physical delivery strategies, but they often fail to control the delivery of genes in targeting regions, and thus lead to off-target side effects. Although endogenous biochemical signal-responsive carriers have been used to improve the transfection efficiency, their selectivity and specificity are still poor because of the coexistence of biochemical signals in both normal tissues and disease sites. In contrast, light-responsive carriers can be adopted to precisely control gene transgenic behaviors at the specified locations and time, thus reducing the off-target gene editing at nontarget positions. Particularly, the near-infrared (NIR) light has better tissue penetration depth and lower phototoxicity than ultraviolet and visible light sources, showing great promise for intracellular gene expression regulation. In this review, we summarize the recent progress of NIR photoresponsive nanotransducers for precision regulation of gene expression. These nanotransducers can achieve controlled gene expression via three different mechanisms (photothermal activation, photodynamic regulation, and NIR photoconversion) to allow various applications, such as gene therapy of cancer, which will be discussed in detail. A conclusion and discussion of the challenges and outlook will be given at the end of this review.
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