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Molecular diagnosis and accurate damage analysis of complex genomic DNAs in tumor cells are crucial to the theranostics of cancers but still a huge challenge. Herein, by designed preparation of a uniform plasmonic sunflower-like assembly gold (Au) nanostructure that is capable of efficient DNA capture and providing high-density gap-plasmon “hot spots” for adequate surface-enhanced Raman spectroscopy (SERS) enhancement, we succeeded in sensitive and reliable label-free SERS detection of DNA damage in electrostimulus-induced apoptotic cancer cells at the DNA base level for the first time. The SERS results showed that the external electrostimulus (at 1.2 V, for 5 min) was almost harmless to normal healthy cells, but it caused pronounced double strand break and adenine base damage in cancer cell DNAs, which effectively destroyed the reproduction and transcription of DNAs and ultimately induced cell apoptosis. The developed sensing platform and method are promising for cell study of genetically related diseases.

Monitoring externalization of phosphatidylserine (PS) and gaining insights into molecular events of cell membrane damage are significant for programmed cell death studies. Herein, by encapsulating zeolitic imidazole frameworks-8 with plasmonic gold nanoparticles to form micron-nano composites and using them as a single-particle surface-enhanced Raman spectroscopy (SERS) substrate, we succeeded in real-time discriminating and monitoring the externalization of PS on cell membranes during electrostimulus-induced apoptosis. The micron-nano composite probe provides rich "hot spots" and robust anchoring capacity for cell membranes, achieving the capture and label-free single-particle SERS detection of the externalized PS. By this method, the dynamic PS externalization process differences between cancerous cells and normal cells were clearly revealed of which the cell membrane damage of cancerous cells was more serious than that of normal cells. This method is versatile and robust for monitoring the externalization of PS and uncovering related cell membrane damage mechanisms. This work also broadens the application of metal−organic framework materials for advanced biomedical applications.

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Caspase-3 is considered as one of the key proteases that can spontaneously regulate the life activities of cells, and its activation (usually is a slow process) will execute the apoptosis process of cells. Rapid activation of caspase-3 on demand in living-cells is therefore highly desired toward precise cancer therapy but it is still a key challenge. Herein, we applied electrostimulus (ES) to achieve fast activation of caspase-3 and trigger cell apoptosis, and developed a smart magnetic-plasmonic assembly nanoprobes (A-nanoprobes) to real-time trace cellular caspase-3 activation at the single cell level. The designer core–satellite A-nanoprobe, working specific to the activated caspase-3 via a disassembly tactic, provides strong “hot spots” to improve the sensitivity and therefore enables SERS sensing of cellular caspase-3 upon activated by ES. Single-cell analysis revealed that the ES can rapidly activate the apoptosis pathway of caspase-3 on demand to make the DNA fragmentation and ultimately induce the cell apoptosis. Such method and nanoplatform were further used to monitor ES-triggered caspase-3 activation in cell apoptosis process of different cell types, revealing that more caspase-3 will be activated for cancerous cells than normal cells during the ES to induce cells apoptosis. This strategy and platform are promising for detecting cellular caspase-3 and other enzymes in the process of cancer diagnosis and treatments.

Integration of disease diagnosis and therapy in vivo by nanotechnology is a challenge in the design of multifunctional nanocarriers. Herein, we report an intelligent and degradable nanoreactor, an assembly of the 4-mercaptobenzonitrile-decorated silver nanoparticles (AgNPs@MBN) and the glucose oxidase (GOx)-loaded metal-organic-framework (ZIF-8@GOx), which can be activated by tumor microenvironment to start the catalytic cascade-enhanced chemo-starvation synergistic therapy and simultaneous self-sense of cellular glucose level. Under the mild acidic microenvironment of tumor, the nanoreactor will collapse to release GOx that triggers a catalytic cascade reaction in vivo, depleting glucose, etching AgNPs@MBN, and producing toxic H 2 O 2 , Ag + , and Zn 2+ ions, all of which work together to inhibit tumor growth. The AgNPs@MBN as SERS nanoprobe reads out glucose concentration noninvasively in tumor to achieve instant feedback of therapeutic progression. This work proposes a promising example of using enzyme-encapsulated biomineralized MOFs as an effective anticarcinogen for clinical applications.Recently, glucose oxidase (GOx)-based cancer starvation therapy that depletes glucose and engenders toxic H 2 O 2 /gluconic acid in the presence of oxygen has been explored (Chang et al., 2017;Wang et al., 2016; Zhang et al., 2018a) as a targeting therapeutic strategy for cancers due to its powerful ability to change tumor microenvironments. Moreover, the generated H 2 O 2 not only markedly enhances tumor oxidative stress but also can be converted into $OH radicals to kill cancer cells (Wang et al., 2019b). Thus this strategy can be further integrated with other therapeutic methods to achieve enhanced synergistic therapeutic effects (Wang et al., 2019c;Ma et al., 2019;Tang et al., 2019). The naked GOx exposed in biological environments is particularly prone to inactivation. Also, it has the weaknesses of short in vivo half-life, immunogenicity, and systematic toxicity (Fu et al., 2018). Thus, nanocarriers (inorganic or organic) for GOx (Wang et al., 2016; Zhang et al., 2018a) are highly suggested in many GOx-based starvation therapeutic strategies. However, these nanocarriers are usually undegradable in vivo, and hence may cause biotoxicity. Therefore, a degradable and intelligent nanocarrier for precise GOx-based starvation therapy is urgently desired.Metal-organic frameworks (MOFs) are a class of highly crystalline, porous, and degradable solid-state materials constructed by metal ions and organic linkers (Wang et al., 2019a;Schoedel et al., 2016). It affords a promising biomedical nanocarrier platform for encapsulating drugs, antibodies, genes, enzymes, etc. (Feng et al., 2018;Chen et al., 2019) for in vivo drug delivery. These MOF cages can protect proteins from the attack of proteases and the clearance of the mononuclear phagocyte system in physiological environments (

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Disulfiram (DSF) is a clinical antialcoholism drug that has been confirmed to show anticancer bioactivity after chelating with Cu2+. Therefore, how to co-deliver DSF and Cu2+ to tumor tissues and generate a smart response to the tumor microenvironment (TME) are the focus of repurposing DSF for the effective treatment of cancer. Herein, we fabricated facilely a smart nanosystem by coating tannic acid (TA) and Cu2+ network on DSF, denoted as DSF@TA–Cu, which responses well to TME and forms CuET complex in situ. In such a way, besides the chemotherapy effect of CuET, the anticancer efficacy of the resulting nano-prodrug can further be augmented by a continuous Fenton-like reaction. We then tested the cytotoxicity DSF@TA–Cu with normal and cancerous cell lines. Finally, by constructing mitochondria-targeted nanoprobes, we monitored the changes in mitochondrial metabolism and explored the lethal mechanisms in A549 cells. We found that DSF@TA–Cu showed higher toxicity to cancerous cells. By analyzing the fluorescence images and surface-enhanced Raman scattering (SERS) spectra of mitochondria, we found that the DNA damage and the decrease in mitochondrial membrane potential (MMP) were closely related to the generation and accumulation of reactive oxygen species (ROS). Although activated related pathways try to counteract the effects of elevation of ROS, excessive ROS inevitably leads to apoptosis of cancer cells.