Synthetic lethality was proposed nearly a century ago by geneticists and recently applied to develop precision anticancer therapies. To exploit the synthetic lethality concept in the design of chemical anticancer agents, we developed a bioorthogonally catalyzed lethality (BCL) strategy to generate targeting antitumor metallodrugs both in vitro and in vivo. Metallodrug Ru-rhein was generated from two nontoxic species Ru-N3 and rhein-alkyne via exclusive endogenous copper-catalyzed azide alkyne cycloaddition (CuAAC) reaction without the need of an external copper catalyst. The nontoxic species Ru-arene complex Ru-N3 and rhein-alkyne were designed to perform this strategy, and the mitochondrial targeting product Ru-rhein was generated in high yield (> 83%) and showed high antitumor efficacy in vitro. This BCL strategy achieved a remarkable tumor suppression effect on the tumor-bearing mice models. It is interesting that the combination of metal-arene complexes with rhein via CuAAC reaction could transform two nontoxic species into a targeting anticancer metallodrug both in vitro and in vivo, while the product Ru-rhein was nontoxic towards normal cells. This is the first example that exclusive endogenous copper was used to generate metal-based anticancer drugs for cancer treatment. The anticancer mechanism of Ru-rhein was studied and autophagy was induced by increased reactive oxygen species and mitochondrial damage. The generality of this BCL strategy was also studied and it could be extended to other metal complexes such as Os-arene and Ir-arene complexes. Compared with the traditional methods for cancer treatment, this work presented a new approach to generate targeting metallodrugs in vivo via the BCL strategy from nontoxic species in the metal-based chemotherapy.
Nanozyme‐driven catalytic antibacterial therapy has become a promising modality for bacterial biofilm infections. However, current catalytic therapy of biofilm wounds is severely limited by insufficient catalytic efficiency, excessive inflammation, and deep tissue infection. Drawing from the homing mechanism of natural macrophages, herein, a hollow mesoporous biomimetic single‐atomic nanozyme (SAN) is fabricated to actively target inflamed parts, suppress inflammatory factors, and eliminate deeply organized bacteria for enhance biofilm eradication. In the formulation, this biomimetic nanozyme (Co@SAHSs@IL‐4@RCM) consists of IL‐4‐loaded cobalt SANs‐embedded hollow sphere encapsulate by RAW 264.7 cell membrane (RCM). Upon accumulation at the infected sites through the specific receptors of RCM, Co@SAHS catalyze the conversion of hydrogen peroxide into hydroxyl radicals and are further amplify by NIR‐II photothermal effect and glutathione depletion to permeate and destroy biofilm structure. This behavior subsequently causes the dissociation of RCM shell and the ensuing release of IL‐4 that can reprogram macrophages, enabling suppression of oxidative injury and tissue inflammation. The work paves the way to engineer alternative “all‐in‐one” SANs with an immunomodulatory ability and offers novel insights into the design of bioinspired materials.
Breast cancer (BC) is one of the most common malignant tumor and often accompanied by inflammatory processes. Inflammation is an essential component of the tumor microenvironment, which might influence the...
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