Iron (II)-based metal-organic framework nanozyme for boosting tumor ferroptosis through inhibiting DNA damage repair and system Xc.

Development of ferroptosis-inducible nanoplatforms with high efficiency and specificity is highly needed and challenging in tumor ferrotherapy. Here, we demonstrate highly effective tumor ferrotherapy using iron (II)-based metal-organic framework (FessMOF) nanoparticles, assembled from disulfide bonds and ferrous ions. The as-prepared FessMOF nanoparticles exhibit peroxidase-like activity and pH/glutathione-dependent degradability, which enables tumor-responsive catalytic therapy and glutathione depletion by the thiol/disulfide exchange to suppress glutathione peroxidase 4, respectively. Upon PEGylation and Actinomycin D (ActD) loading, the resulting FessMOF/ActD-PEG nanoplatform induces marked DNA damage and lipid peroxidation. Concurrently, we found that ActD can inhibit Xc- system and elicit ferritinophagy, which further boosts the ferrotherapeutic efficacy of the FessMOF/ActD-PEG. In vivo experiments demonstrate that our fabricated nanoplatform presents excellent biocompatibility and a high tumor inhibition rate of 91.89%.

Mitochondrial-Targeted Copper Delivery for Cuproptosis-Based Synergistic Cancer Therapy.

Cuproptosis is dependent on mitochondrial respiration modulation by targeting lipoylated tricarboxylic acid cycle (TCA) cycle proteins, showing great potential in cancer treatment. However, the specific release of copper ions at mitochondrial is highly needed and still a major challenge to trigger cellular cuproptosis. Herein, a metal-organic framework-based nanoplatform (ZCProP) is designed for mitochondrial-targeted and ATP/pH-responsive Cu2+ and prodigiosin release. The released Cu2+ promotes aggregation of lipoylated protein and loss of Fe-S cluster protein, resulting in cell cuproptosis. In the meanwhile, Cu2+ can concert with prodigiosin to induce mitochondrial dysfunction and DNA damage and enhance cell cuproptosis. Furthermore, this nanoplatform has an ability to deplete glutathione, which not only further promotes cuproptosis but also triggers cell ferroptosis by the suppression of glutathione peroxidase 4, an anti-ferroptosis protein. Collectively, the designed ZCProP nanoplatform can responsively release cargos at mitochondrial and realize a conspicuous therapeutic efficacy through a cuproptosis-mediated concerted effect. Along with its excellent biocompatibility, this nanoplatform may provide a novel therapeutic modality paradigm to boost cancer therapeutic strategies based on cuproptosis.

Engineered Microbial Nanohybrids for Tumor-Mediated NIR II Photothermal Enhanced Ferroptosis/Cuproptosis and Immunotherapy.

The colon tumor microenvironment has a high concentration of H2 S and glutathione, which is highly immunosuppressive and adverse to multiple therapeutic methodologies such as ferroptosis. Here, an engineered microbial nanohybrid based on Escherichia coli (E. coli) and Cu2 O nanoparticles to specific colon tumor therapy and immunosuppression reversion is reported. The as-prepared E. coli@Cu2 O hybrid can accumulate in tumor sites upon intravenous injection, and Cu2 O nanoparticles convert to Cux S by consuming the endogenous H2 S, which exhibits strong photothermal conversion at near-infrared II (NIR II) biological window. Furthermore, E. coli@Cu2 O is able to induce cellular ferroptosis and cuproptosis through inactivation of glutathione peroxidase 4 and aggregation of dihydrolipoamide S-acetyltransferase, respectively. Photothermal-enhanced ferroptosis/cuproptosis achieved by E. coli@Cu2 O reverses the immunosuppression of colon tumors by triggering dendritic cell maturation (about 30%) and T cell activation (about 50% CD8+ T cells). Concerted with immune checkpoint blockade, the engineered microbial nanohybrid can inhibit the growth of abscopal tumors upon NIR illumination. Overall, the designed microbial nanohybrid can achieve tumor-specific photothermal-enhanced ferroptosis/cuproptosis and immunosuppression reversion, showing promise in precise tumor therapy in future clinical translation.

In situ generation of hybrid alginate hydrogels for enhanced breast tumor ferrotherapy through multiplex magnifying redox imbalances.

Ferroptosis has drawn great attention to tumor treatments over the past decade. However, how to specifically boost tumoral redox imbalance by simultaneously superimposing iron-mediated reactive oxygen species and undermining antioxidative pathways at the tumor site is still a significant challenge in ferroptosis-based tumor ferrotherapy. In this study, we designed an in situ generable hydrogel that contains paclitaxel/chlorin e6-loaded iron-based metal-organic framework (Fe-MOF) nanoparticles for enhanced breast tumor ferrotherapy by multiplex magnifying redox imbalance. The polysaccharide sodium alginate can crosslink with tumoral calcium ions to generate a hydrogel patch, which promotes the retention of Fe-MOF and therapeutic molecules. The Fe-MOF holds peroxidase/glutathione oxidase mimicking properties, resulting in OH generation via the Fenton reaction and glutathione consumption. Local ultrasound treatment facilitates the release of therapeutics and stimulates the generation of signet oxygen by activating the sonosensitizer chlorin e6. In the meanwhile, the low-dose paclitaxel reduces tumoral pH value by downregulating the glutaminolysis-related gene (SLC7A11) which in turn enhances the catalytic activity of Fe-MOF and inhibits antioxidative pathways, respectively. Both in vivo and in vitro experiments show that our designed hybrid hydrogels can induce significant ferrotherapeutic effects by augmenting the tumoral oxidative stresses.

Synergistic glycolysis disturbance for cancer therapy by a MOF-based nanospoiler.

Increased glycolysis for promoting adenosine triphosphate (ATP) generation is one of the hallmarks of cancer. Although reducing glucose intake or depriving cellular glucose can delay the growth of tumors to some extent, their therapeutic efficacy is a highly needed improvement for clinical translation. Herein, we found that mannose synergistic with glucose oxidase (GOx) can induce cell death by ATP inhibition, autophagy activation, and apoptosis protein upgradation. By using biodegradable zeolitic imidazolate frameworks (ZIF-8) as a nanocarrier (denoted as ZIF-8/M&G), the mannose and GOx can accumulate at the tumor site while having no obvious long-term toxicity. At the tumor site, GOx inhibits glycolysis by converting glucose and oxygen to H 2O 2 and gluconic acid, realizing oxidation therapy and expediting the degradation of the pH-responsive ZIF-8 nanoparticles, respectively. Simultaneously, mannose disturbs sugar metabolism and reduces oxygen consumption, which in turn promotes the GOx oxidation process. The concerted glycolysis inhibition through interactions between mannose and GOx endows ZIF-8/M&G nanospolier with excellent therapeutic efficacy both in vitro and in vivo. Synergistic glycolysis disturbance by the designed nanospoiler in this work proposes a versatile approach for metabolism disturbance to tumor treatment.

Glycolysis inhibition for synergistic phototherapy of triple-negative breast cancer.

Phototherapy is a local and precise therapeutic technique for tumor treatment. However, the therapeutic effects of photothermal and photodynamic therapies are inevitably encountered by hypoxia of the tumor microenvironment and heat shock protein induced by hyperthermia, respectively. Herein, we found that mannose, a glucose analog, could reverse tumor hypoxia by inhibiting glycolysis of cancer cells and suppressing the expression of heat shock protein through inhibiting cellular adenosine triphosphate (ATP) generation. Next, we used lipid nanoparticles simultaneously loaded with indocyanine green (ICG) and mannose molecules, named imLipo, for tumor therapy. Both in vitro and in vivo experiments evidenced that the imLipo nanoplatform has significant therapeutic efficacy through synergistic phototherapy under single near-infrared laser irradiation. This work shows that glycolysis inhibition can overcome the challenges of phototherapy. In addition, all three parts (mannose, ICG, and lipid) of imLipo are clinically approved and our designed nanoplatforms have great potential for future tumor treatment.

Enantiospecific Detection of D-Amino Acid through Synergistic Upconversion Energy Transfer.

D-amino acids (DAAs) are indispensable in regulating diverse metabolic pathways. Selective and sensitive detection of DAAs is crucial for understanding the complexity of metabolic processes and managing associated diseases. However, current DAA detection strategies mainly rely on bulky instrumentation or electrochemical probes, limiting their cellular and animal applications. Here we report an enzyme-coupled nanoprobe that can detect enantiospecific DAAs through synergistic energy transfer. This nanoprobe offers near-infrared upconversion capability, a wide dynamic detection range, and a detection limit of 2.2 µM, providing a versatile platform for in vivo noninvasive detection of DAAs with high enantioselectivity. These results potentially allow real-time monitoring of biomolecular handedness in living animals, as well as developing antipsychotic treatment strategies.

Combating the Coronavirus Pandemic: Early Detection, Medical Treatment, and a Concerted Effort by the Global Community.

The World Health Organization (WHO) has declared the outbreak of 2019 novel coronavirus, known as 2019-nCoV, a pandemic, as the coronavirus has now infected over 2.6 million people globally and caused more than 185,000 fatalities as of April 23, 2020. Coronavirus disease 2019 (COVID-19) causes a respiratory illness with symptoms such as dry cough, fever, sudden loss of smell, and, in more severe cases, difficulty breathing. To date, there is no specific vaccine or treatment proven effective against this viral disease. Early and accurate diagnosis of COVID-19 is thus critical to curbing its spread and improving health outcomes. Reverse transcription-polymerase chain reaction (RT-PCR) is commonly used to detect the presence of COVID-19. Other techniques, such as recombinase polymerase amplification (RPA), loop-mediated isothermal amplification (LAMP), clustered regularly interspaced short palindromic repeats (CRISPR), and microfluidics, have allowed better disease diagnosis. Here, as part of the effort to expand screening capacity, we review advances and challenges in the rapid detection of COVID-19 by targeting nucleic acids, antigens, or antibodies. We also summarize potential treatments and vaccines against COVID-19 and discuss ongoing clinical trials of interventions to reduce viral progression.

AIEgen-coupled upconversion nanoparticles eradicate solid tumors through dual-mode ROS activation.

Reactive oxygen species (ROS) are essential for the regulation of antitumor immune responses, where they could induce immunogenic cell death, promote antigen presentation, and activate immune cells. Here, we report the development of near-infrared (NIR)-driven immunostimulants, based on coupling upconversion nanoparticles with aggregation-induced emission luminogens (AIEgens), to integrate the immunological effects of ROS for enhanced adaptive antitumor immune responses. Intratumorally injected AIEgen-upconversion nanoparticles produce high-dose ROS under high-power NIR irradiation, which induces immunogenic cell death and antigen release. These nanoparticles can also capture the released antigens and deliver them to lymph nodes. Upon subsequent low-power NIR treatment of lymph nodes, low-dose ROS are generated to further trigger efficient T cell immune responses through activation of dendritic cells, preventing both local tumor recurrence and distant tumor growth. The utility of dual-mode pumping power on AIEgen-coupled upconversion nanoparticles offers a powerful and controllable platform to activate adaptive immune systems for tumor immunotherapy.

Biomineralization of Bacteria by a Metal-Organic Framework for Therapeutic Delivery.

Biomimetic mineralization of live organisms shows extraordinary promise in biotechnology. However, their therapeutic applications have been insufficiently explored. Herein, it is demonstrated that metal-organic framework (MOF)-engineered bacteria are powerful carriers for tumor-targeted therapeutic delivery. Specifically, Escherichia coli (MG1655) is coated with a zeolitic imidazolate framework-8 layer coloaded with a photosensitizer and chemical drug through a one-step in situ method. The as-prepared bacteria@MOF hybrid preserves its viability and tumor selectivity. It exhibits high therapeutic efficacy both in vitro and in vivo in a combined chemo-photodynamic manner. To the best of knowledge, this is the first report of engineered bacteria@MOFs for in vivo tumor treatment. This study opens a new horizon for the bioapplications of biomineralized organisms and may provide novel strategies against tumors.

Improving Cancer Immunotherapy Outcomes Using Biomaterials.

Immunotherapy has made great strides in improving clinical outcomes in cancer treatment. However, few patients exhibit adequate response rates for key outcome measures and desired long-term responses, and they often suffer systemic side effects due to the dynamic nature of the immune system. This has motivated a search for alternative strategies to improve unsatisfactory immunotherapeutic outcomes. In recent years, biomaterial-assisted immunotherapy has shown promise in cancer treatment with improved therapeutic efficacy and reduced side effects. These biomaterials have illuminated fundamental mechanisms underlying the immunoediting process, while greatly improving the efficacy of chimeric antigen receptor (CAR) T-cell therapy, cancer vaccine therapy, and immune checkpoint blockade therapy. This Minireview discusses recent advances in engineered biomaterials that address limitations associated with conventional cancer immunotherapies.

"All-in-One" Silver Nanoprism Platform for Targeted Tumor Theranostics.

Designing a multifunctional theranostic nanoplatform with optional therapeutic strategies is highly desirable to select the most suitable therapeutic manners for the patient's cancer treatment. Among all shapes of silver materials, a silver nanoprism was reported to have great potential in photothermal therapy (PTT) owing to its strong surface plasmon resonance band in the near-infrared region. However, its instability in physicochemical environments and its severe toxicity confined its further application. To overcome this, herein, we demonstrated a silver prism-polydopamine (PDA) hybrid nanoplatform for tumor treatment with three therapeutic strategies. Specifically, the PDA coating endows the silver prism with excellent stability, high photothermal conversion, long-term in vivo biocompatibility, ease of decorating targeting ligands, and drug delivery. Upon near-infrared laser irradiation (808 nm, 1 W/cm2), tumors can be eradicated by the as-prepared nanoparticle through monomodal PTT. Besides, when combined with a chemical drug, this nanoparticle is able to inhibit tumor growth via combined photochemotherapy under a lower laser treatment (0.7 W/cm2). Furthermore, by supplementing with an immune checkpoint blockade, the realized synergistic photochemoimmunotherapy exhibits high efficacy to inhibit tumor relapse and metastasis. Moreover, owing to the high photothermal conversion efficiency and great X-ray attenuation ability of the silver nanoprism, our designed nanoplatform can be used in photoacoustic, computed tomography, and infrared thermal multimodal imaging. Our study provides a multifunctional nanoparticle for tumor theranostics, and this therapeutic strategy-optional nanoplatform shows promise in future biomedicine.

Activating Antitumor Immunity and Antimetastatic Effect Through Polydopamine-Encapsulated Core-Shell Upconversion Nanoparticles.

Synergistic phototherapy has the potential to conquer the extreme heterogeneity and complexity of difficult tumors and result in better cancer treatment outcomes than monomodal photodynamic therapy (PDT) or photothermal therapy (PTT). However, the previous approaches to combining PDT and PTT are mainly focused on primary tumor obliteration while neglecting tumor metastasis, which is responsible for about 90% of cancer deaths. It is shown that a combined PDT/PTT approach, based on upconversion-polymer hybrid nanoparticles with surface-loaded chlorin e6 photosensitizer, can enhance primary tumor elimination and elicit antitumor immunity against disseminated tumors. The specifical arrangement of an external upconversion coating over the polymer core ensures adequate photoabsorption by the upconversion nanoparticles for the generation of reactive oxygen species upon single near-infrared light irradiation. Furthermore, it is found that synergistic phototherapy can elicit robust systemic and humoral antitumor immune responses. When combined with immune checkpoint blockades, it can inhibit tumor relapse and metastasis as well as prolong the survival of tumor-bearing mice in two types of tumor metastasis models. This study may establish a new modality for enhancing immunogenic cell death through a synergistic phototherapeutic nanoplatform and extend this strategy to overcome tumor metastasis with an augmented antitumor immune response.

Dynamic Microfluidic Cytometry for Single-Cell Cellomics: High-Throughput Probing Single-Cell-Resolution Signaling.

Cell signaling is a fast, dynamic, and complex process, which controls a variety of critical physiological functions. Methods to investigate such dynamic information, however, suffer from limited throughput in the single-cell level and a lack of precise fluid manipulation. Herein, we present a new strategy, termed dynamic microfluidic cytometry (DMC), for high-throughput probing of G protein-coupled receptor (GPCR) signaling in single-cell resolution (single-cell cellomics analysis) by creatively applied cyclical cell trapping, stimulating, and releasing automatically. Dose-response curves and half-maximal effective concentration (EC50) values for HeLa cells treated with adenosine triphosphate (ATP), histamine (HA), and acetylcholine chloride (ACH) were successfully obtained in the single-cell level. High-throughput single-cell dynamic signaling was further implemented by sequential or simultaneous stimulation, which revealed that different mechanisms were working in triggering intracellular calcium release. In addition, simultaneous stimulation to two different types of cells, HeLa and NIH-3T3 cells, was also successfully realized, which was crucial for online comparison of dynamic signaling of different types of cells. We believe that the proposed DMC provides a versatile means for high-throughput probing single-cell dynamic signaling, which is potentially useful in chemical biology, cell biology, and pharmacology.

Integrated Multifunctional Electrochemistry Microchip for Highly Efficient Capture, Release, Lysis, and Analysis of Circulating Tumor Cells.

The circulating tumor cells (CTCs) in the blood allow the noninvasive analysis of metastatic mechanisms, cancer diagnosis, prognosis, disease monitoring, and precise therapy through "liquid biopsies". However, there is no integrated and robust multifunctional microchip, which not only could highly efficient capture CTCs, but also fast release and lyse cells on one single chip without using other biochemical agents for downstream biomedical analysis. In this work, we integrated the three functions in one electrochemical microchip (echip) by intentionally designing a cactus-like, topologically structured conductive array consisted of a PDMS micropillar-array core and an electroconductive gold coating layer with hierarchical structure. The echip presented a capture efficiency of 85-100% for different cell lines in both buffer solution and whole blood. Moreover, the validity of the echip was further evaluated by using non-small-cell lung cancer patient samples. The electrochemical released cells or lysed-cell solutions could be obtained within 10 min and have been successfully used for mutant detection by DNA sequencing or RT-PCR. The fast release at a relative low voltage (-1.2 V) was originating from an electrochemical cleavage of the Au-S bonds that immobilized antibody on the chip. The electrochemical lysis took place at a high voltage (20 V) with an admirable performance. Thus, the highly integrated multifunctional echip was well demonstrated and promised a significant application in the clinical field.

Microfluidic Chemical Function Generator for Probing Dynamic Cell Signaling.

Cellular environments are inherently dynamic and generally involve complex, temporally varying signals. Reconstruction of these environments with high spatial and temporal fidelity and simultaneous imaging of intracellular dynamics in live cells remains a major challenge. In this paper, a microfluidic chemical function generator (µCFG) was proposed for probing cell dynamic signaling with high temporal resolution. By combining a hydrodynamic gating module with a chaotic advection mixing module, the µCFG was able to generate a variety of chemical waveforms, such as digital pulsatile chemical waveforms with a frequency higher than 10 Hz and analog chemical waveforms with a frequency higher than 0.2 Hz. The shape, frequency, amplitude, and duty cycle of the waveforms could be also conveniently modulated. To demonstrate the capability of µCFG of probing fast biological processes and elucidate signal transduction pathways in complex signaling networks, a variety of temporal responses of Ca2+ signaling to ATP-induced activation of the P2Y receptor, a prototypical G-protein coupled receptor (GPCR), were investigated in live cells by precisely and dynamically controlling their microenvironment.

Monte Carlo Modeling-Based Digital Loop-Mediated Isothermal Amplification on a Spiral Chip for Absolute Quantification of Nucleic Acids.

Digital loop-mediated isothermal amplification (dLAMP) is an attractive approach for absolute quantification of nucleic acids with high sensitivity and selectivity. Theoretical and numerical analysis of dLAMP provides necessary guidance for the design and analysis of dLAMP devices. In this work, a mathematical model was proposed on the basis of the Monte Carlo method and the theories of Poisson statistics and chemometrics. To examine the established model, we fabricated a spiral chip with 1200 uniform and discrete reaction chambers (9.6 nL) for absolute quantification of pathogenic DNA samples by dLAMP. Under the optimized conditions, dLAMP analysis on the spiral chip realized quantification of nucleic acids spanning over 4 orders of magnitude in concentration with sensitivity as low as 8.7 × 10-2 copies/µL in 40 min. The experimental results were consistent with the proposed mathematical model, which could provide useful guideline for future development of dLAMP devices.

Rhipsalis (Cactaceae)-like Hierarchical Structure Based Microfluidic Chip for Highly Efficient Isolation of Rare Cancer Cells.

The circulating tumor cells (CTCs), originating from the primary tumor, play a vital role in cancer diagnosis, prognosis, disease monitoring, and precise therapy. However, the CTCs are extremely rare in the peripheral bloodstream and hard to be isolated. To overcome current limitations associated with CTC capture and analysis, the strategy incorporating nanostructures with microfluidic devices receives wide attention. Here, we demonstrated a three-dimensional microfluidic device (Rm-chip) for capturing cancer cells with high efficiency by integrating a novel hierarchical structure, the "Rhipsalis (Cactaceae)"-like micropillar array, into the Rm-chip. The PDMS micropillar array was fabricated by soft-lithography and rapid prototyping method, which was then conformally plated with a thin gold layer through electroless plating. EpCAM antibody was modified onto the surface of the micropillars through the thiol-oligonucleotide linkers in order to release captured cancer cells by DNase I treatment. The antibody-functionalized device achieved an average capture efficiency of 88% in PBS and 83.7% in whole blood samples. We believe the Rm-chip provided a convenient, economical, and versatile approach for cell analysis with wide potential applications.

Rapid Assembly of Heterogeneous 3D Cell Microenvironments in a Microgel Array.

Heterogeneous 3D cell microenvironment arrays are rapidly assembled by combining surface-wettability-guided assembly and microdroplet-array-based operations. This approach enables precise control over individual shapes, sizes, chemical concentrations, cell density, and 3D spatial distribution of multiple components. This technique provides a cost-effective solution to meet the increasing demand of stem cell research, tissue engineering, and drug screening.