Liquid Metal as Bioinspired and Unusual Modulator in Bioorthogonal Catalysis for Tumor Inhibition Therapy.

Bioorthogonal catalysis mediated by Pd-based transition metal catalysts has sparked increasing interest in combating diseases. However, the catalytic and therapeutic efficiency of current Pd0 catalysts is unsatisfactory. Herein, inspired by the concept that ligands around metal sites could enable enzymes to catalyze astonishing reactions by changing their electronic environment, a LM-Pd catalyst with liquid metal (LM) as an unusual modulator has been designed to realize efficient bioorthogonal catalysis for tumor inhibition. The LM matrix can serve as a "ligand" to afford an electron-rich environment to stabilize the active Pd0 and promote nucleophilic turnover of the π-allylpalladium species to accelerate the uncaging process. Besides, the photothermal properties of LM can lead to the enhanced removal of tumor cells by photo-enhanced catalysis and photothermal effect. We believe that our work will broaden the application of LM and motivate the design of bioinspired bioorthogonal catalysts.

DNA-based platform for efficient and precisely targeted bioorthogonal catalysis in living systems.

As one of the typical bioorthogonal reactions, copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction holds great potential in organic synthesis, bioconjugation, and surface functionalization. However, the toxicity of Cu(I), inefficient catalytic activity, and the lack of cell specific targeting of the existing catalysts hampered their practical applications in living systems. Herein, we design and construct a DNA-based platform as a biocompatible, highly efficient, and precisely targeted bioorthogonal nanocatalyst. The nanocatalyst presents excellent catalytic efficiency in vitro, which is one order of magnitude higher than the commonly used catalyst CuSO4/sodium ascorbate. The theoretical calculation further supports the contribution of DNA structure and its interaction with substrates to the superior catalytic activity. More importantly, the system can achieve efficient prodrug activation in cancer cells through cell type-specific recognition and produce a 40-fold enhancement of transformation compared to the non-targeting nanocatalyst, resulting in enhanced antitumor efficacy and reduced adverse effects. In vivo tumor therapy demonstrates the safety and efficacy of the system in mammals.

Self-Adaptive Single-Atom Catalyst Boosting Selective Ferroptosis in Tumor Cells.

Ferroptosis, resulting from the catastrophic accumulation of lipid reactive oxygen species (ROS) and the inactivation of glutathione (GSH)-dependent peroxidase 4 (GPX4), has emerged as a form of regulated cell death for cancer therapy. Despite progress made with current ferroptosis inducers, efficient systems to trigger ferroptosis remain challenging, owing largely to their low activity, uncontrollable behavior, and even nonselective interactions. Here, we report a self-adaptive ferroptosis platform by engineering a DNA modulator onto the surface of single-atom nanozymes (SAzymes). The modulator could not only specifically intensify the ROS-generating activity but also endow the SAzymes with on-demand GSH-consuming ability in tumor cells, accelerating selective and safe ferroptosis. The self-adaptive antitumor response has been demonstrated in colon cancer and breast cancer, promoting the development of selective cancer therapy.

Remodeling Macrophages by an Iron Nanotrap for Tumor Growth Suppression.

Tumor-associated macrophages (TAMs) that infiltrate in most tumor tissues are closely correlated with proliferation and metastasis of tumor cells. Immunomodulation of TAMs from pro-tumorigenic M2 phenotype to anti-tumorigenic M1 phenotype is crucial for oncotherapy. Herein, an iron nanotrap was utilized to remodel TAMs for tumor growth inhibition. In the formulation, the ultrasmall nanotrap could capture and targetedly transport endogenous iron into TAMs even inside the tumor. Upon exposing to the lysosomal acidic conditions and intracellular H2O2, iron was released from the nanotrap and produced the generation of oxidative stress, which could reprogram TAMs. The activated M1 macrophages could induce immune responses and suppress tumor growth ultimately. Meanwhile, this metal-free nanotrap with degradability by H2O2 possessed favorable biocompatibility. Our work would present potential opportunities of utilizing endogenous substances for secure treatment of various diseases.

MicroRNA-Triggered Nanozymes Cascade Reaction for Tumor-Specific Chemodynamic Therapy.

Off-target toxicity and insufficient hydroxyl radicals (. OH) generation limit the further clinical application of nanozymes in chemodynamic therapy (CDT). Herein, we designed and constructed a microRNA-triggered nanozyme cascade platform for enhanced tumor-specific chemodynamic therapy. The nanozyme-based cascade reaction could be triggered successfully by the high expression of microRNA in cancer cells to generate more . OH, thus exhibiting excellent tumor-specific therapeutic performance. Our work provides a new dimension for tumor-specific chemodynamic therapy.

Cell membrane-camouflaged liposomes for tumor cell-selective glycans engineering and imaging in vivo.

The dynamic change of cell-surface glycans is involved in diverse biological and pathological events such as oncogenesis and metastasis. Despite tremendous efforts, it remains a great challenge to selectively distinguish and label glycans of different cancer cells or cancer subtypes. Inspired by biomimetic cell membrane-coating technology, herein, we construct pH-responsive azidosugar liposomes camouflaged with natural cancer-cell membrane for tumor cell-selective glycan engineering. With cancer cell-membrane camouflage, the biomimetic liposomes can prevent protein corona formation and evade phagocytosis of macrophages, facilitating metabolic glycans labeling in vivo. More importantly, due to multiple membrane receptors, the biomimetic liposomes have prominent cell selectivity to homotypic cancer cells, showing higher glycan-labeling efficacy than a single-ligand targeting strategy. Further in vitro and in vivo experiments indicate that cancer cell membrane-camouflaged azidosugar liposomes not only realize cell-selective glycan imaging of different cancer cells and triple-negative breast cancer subtypes but also do well in labeling metastatic tumors. Meanwhile, the strategy is also applicable to the use of tumor tissue-derived cell membranes, which shows the prospect for individual diagnosis and treatment. This work may pave a way for efficient cancer cell-selective engineering and visualization of glycans in vivo.

Elimination of macrophage-entrapped antibiotic-resistant bacteria by a targeted metal-organic framework-based nanoplatform.

A novel metal-organic framework-based platform was designed and constructed for photosensitizer delivery for the elimination of intracellular antibiotic-resistant bacteria. With the merit of targeting and internalizing ability, the system could kill the stealthy bacteria efficiently under light irradiation.

Nature-Inspired Construction of MOF@COF Nanozyme with Active Sites in Tailored Microenvironment and Pseudopodia-Like Surface for Enhanced Bacterial Inhibition.

Metal-organic frameworks (MOFs) have sparked increasing interest in mimicking the structure and function of natural enzymes. However, their catalytic and therapeutic efficiency are unsatisfactory due to the relatively lower catalytic activity. Herein, inspired by nature, a MOF@COF nanozyme has been designed as a high-efficiency peroxidase mimic, with the metallic nodes of MOFs as active centres, the hierarchical nanocavities produced by the growth of covalent organic frameworks (COFs) as binding pockets to form tailored pore microenvironment around active sites for enriching and activating substrate molecules, to perform enhanced bacterial inhibition. Furthermore, the pseudopodia-like surface of the COFs "skin" enabled the system to catch the bacteria effectively for further amplifying the therapeutic efficiency of MOF-based nanozyme. We believe that the present study will not only facilitate the design of novel nanozymes, but also broaden the biological usage of MOF/COF-based hybrid materials.

Tumor-activatable ultrasmall nanozyme generator for enhanced penetration and deep catalytic therapy.

Tumor-activatable ultrasmall nanozyme generation is an unprecedented strategy to overcome intrinsically fatal defects of traditional reactive oxygen species (ROS)-based nanoagents for deep tumor penetration, including limited tissue-penetrating depth of external energy, heavy reliance on oxygen and nonspecific toxicity of therapeutic agents. Here, based on the cascade reaction between glucose oxidase (GOx) and ultrasmall peroxidase nanozyme embedded into acid-dissociable zeolitic imidazolate framework-8 (ZIF-8), such a tumor-activatable ultrasmall nanozyme generator is designed for enhanced penetration and deep catalytic therapy. With the aid of mildly acidic tumor microenvironment, the produced gluconic acid from intratumoral glucose can gradually induce the dissociation of ZIF-8 to release ultrasmall peroxidase nanozyme with significant intratumoral penetration. On the other hand, the generated hydrogen peroxide with relatively long-life can be subsequently catalyzed by penetrated peroxidase nanozyme into toxic hydroxyl radicals for deep catalytic therapy. In this way, the well-designed nanoplatform not only can greatly enhance tumor penetration but also directly induce exogenous ROS without oxygen participation and external energy input, thereby thoroughly avoiding the inactivation of traditional ROS-based nanoagents in the extremely hypoxic tumor center and finally resulting in remarkable deep catalytic therapy.

Near-Infrared Light Dual-Promoted Heterogeneous Copper Nanocatalyst for Highly Efficient Bioorthogonal Chemistry in Vivo.

Owing to better stability and biosafety, heterogeneous Cu nanoparticles (CuNPs) have been put forward as a promising candidate to complete the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. However, the inherent poor activity of Cu(0) deterred its wide bioapplication. Herein, we employed near-infrared (NIR) light to dual-promote the CuAAC reaction of a biocompatible heterogeneous copper nanocatalyst through photodynamic and photothermal effects in vitro and in vivo. Specifically, the photodynamic activity could promote the conversion of Cu(0) to Cu(I) to accelerate the catalytic process of CuAAC. The high photothermal conversion efficiency (η = 50.6%) could increase the local temperature, further promoting the whole reaction. Then, a drastically increased reaction rate in a living system ranging from cells to nematodes was achieved in our system. Meanwhile, the better antitumor efficacy has determined with in vivo tumor therapy experiments.

Bioinspired Construction of a Nanozyme-Based H2O2 Homeostasis Disruptor for Intensive Chemodynamic Therapy.

The insufficient intracellular H2O2 level in tumor cells is closely associated with the limited efficacy of chemodynamic therapy (CDT). Despite tremendous efforts, engineering CDT agents with a straightforward and secure H2O2 supplying ability remains a great challenge. Inspired by the balance of H2O2 generation and elimination in cancer cells, herein, a nanozyme-based H2O2 homeostasis disruptor is fabricated to elevate the intracellular H2O2 level through facilitating H2O2 production and restraining H2O2 elimination for enhanced CDT. In the formulation, the disruptor with superoxide dismutase-mimicking activity can convert O2•- to H2O2, promoting the production of H2O2. Simultaneously, the suppression of catalase activity and depletion of glutathione by the disruptor weaken the transformation of H2O2 to H2O. Thus, the well-defined system could perturb the H2O2 balance and give rise to the accumulation of H2O2 in cancer cells. The raised H2O2 level would ultimately amplify the Fenton-like reaction-based CDT efficiency. Our work not only paves a way to engineer alternative CDT agents with a H2O2 supplying ability for intensive CDT but also provides new insights into the construction of bioinspired materials.

Remote and reversible control of in vivo bacteria clustering by NIR-driven multivalent upconverting nanosystems.

Achieving remote and reversible control of bacterial cell-cell interactions associated with interference with pathological processes in living systems remains a challenge owing to the complexity of the in vivo microenvironment and the lack of regulation systems. We present, for the first time, the development of a versatile platform to achieve NIR-driven reversible bacterial clustering both in vitro and in vivo. This platform consisted of ß-CD modified UCNP (UCNP-CD) and photochromic azobenzene glycoconjugates (azo-man), which could dynamically display d-mannose bioactive ligands. Specifically, by virtue of the noncovalent yet strong multivalent interactions between bacteria and nanosystems, robust bacterial clusters could be formed even in vivo within 1 h. Upon NIR stimulation, the upconverted emissions from UCNPs triggered the continuous isomerization of azo-man, leading to dissociation of the nanosystems and dispersion of bacterial clusters. Moreover, in vivo pathogenic infection process could be interfered with the NIR-switched bacterial agglutination. Most importantly, the noninvasive and deep-tissue-penetrating nature of NIR made it possible for dynamically regulation of cellular interactions with minimized influence to both normal cells and nature bacteria flora. This strategy would bring new perspectives for anti-virulence therapeutics and in-depth investigations of specific physiological phenomena.

Bioinspired Design of Fe3+ -Doped Mesoporous Carbon Nanospheres for Enhanced Nanozyme Activity.

Nanozymes have received considerable attention as alternatives of natural enzymes. However, the catalytic activity of nanozymes is often lower than that of natural enzymes, which largely limits their applications. Current methods utilized to improve the catalytic efficiency and substrate selectivity of a nanozyme usually have some inherent drawbacks. Herein, a biomimetic strategy was developed to design Fe3+ -doped mesoporous carbon nanospheres (Fe3+ -MCNs) as a horseradish peroxidase (HRP) mimic to realize the structure and function mimicking of natural HRP. In this system, Fe3+ ions could act as catalytic centers and carboxyl-modified mesoporous carbon nanospheres (MCNs-COOH) could be used to bind with substrates. As a result, Fe3+ -MCNs showed higher enzymatic activity than that of Fe3 O4 nanoparticles. Therefore, this strategy can contribute to the development of nanozymes and further understanding of the complicated enzymatic reactions in natural and biological systems.