Strategies to engineer various nanocarrier-based hybrid catalysts for enhanced chemodynamic cancer therapy.

Chemodynamic therapy (CDT) is a newly developed cancer-therapeutic modality that kills cancer cells by the highly toxic hydroxyl radical (˙OH) generated from the in situ triggered Fenton/Fenton-like reactions in an acidic and H2O2-overproduced tumor microenvironment (TME). By taking the advantage of the TME-activated catalytic reaction, CDT enables a highly specific and minimally-invasive cancer treatment without external energy input, whose efficiency mainly depends on the reactant concentrations of both the catalytic ions and H2O2, and the reaction conditions (including pH, temperature, and amount of glutathione). Unfortunately, it suffers from unsatisfactory therapy efficiency for clinical application because of the limited activators (i.e., mild acid pH and insufficient H2O2 content) and overexpressed reducing substance in TME. Currently, various synergistic strategies have been elaborately developed to increase the CDT efficiency by regulating the TME, enhancing the catalytic efficiency of catalysts, or combining with other therapeutic modalities. To realize these strategies, the construction of diverse nanocarriers to deliver Fenton catalysts and cooperatively therapeutic agents to tumors is the key prerequisite, which is now being studied but has not been thoroughly summarized. In particular, nanocarriers that can not only serve as carriers but are also active themselves for therapy are recently attracting increasing attention because of their less risk of toxicity and metabolic burden compared to nanocarriers without therapeutic capabilities. These therapy-active nanocarriers well meet the requirements of an ideal therapy system with maximum multifunctionality but minimal components. From this new perspective, in this review, we comprehensively summarize the very recent research progress on nanocarrier-based systems for enhanced CDT and the strategies of how to integrate various Fenton agents into the nanocarriers, with particular focus on the studies of therapy-active nanocarriers for the construction of CDT catalysts, aiming to guide the design of nanosystems with less components and more functionalities for enhanced CDT. Finally, the challenges and prospects of such a burgeoning cancer-theranostic modality are outlooked to provide inspirations for the further development and clinical translation of CDT.

Leap-Type Response of Redox/Photo-Active Lanthanide-Based Metal-Organic Frameworks for Early and Accurate Screening of Prostate Cancer.

The development of high-accuracy technologies to distinguish the quite tiny concentration change of tumor markers between negative and positive is of vital significance for early screening and diagnosis of cancers, but is still a great challenge for the conventional biosensors because of their "gradual" detection mode. Herein, a unique "leap-type" responsive lanthanide MOF-based biosensor (designated as Tb-CeMOF-X) with defect-mediated redox-/photo-activities is developed for precisely identifying acid phosphatase (ACP), an early pathological marker of prostate cancer (PCa) in serum. The engineered Tb-CeMOF-X probe achieves a bursting switch-on luminescence at the critical concentration of ACP (9 U·L-1), while keeping silent below this threshold, undergoing a qualitative signal change from "zero" to "one" between negative and positive indicators and thus significantly improving the identification precision. Significantly, such "leap-type" response performance can be further edited and amplified by rational defect engineering in the crystal structure to improve the accessibility of active centers, consequently maximizing the detection sensitivity toward ACP in the complex biological media. This study proposes the first paradigm for the development of "leap-type" biosensors with ultra-sensitive differentiation capability between negative and positive, and provides a potentially valuable tool for early and accurate screening of PCa.

A Luminescent 3d-4f-4d MOF Nanoprobe as a Diagnosis Platform for Human Occupational Exposure to Vinyl Chloride Carcinogen.

A luminescent nanoprobe based on a lanthanide-transition heterometallic metal-organic framework (MOF) is first designed for specific detection of urinary thiodiglycolic acid (TDGA) which is the biomarker of carcinogenic vinyl chloride monomer (VCM) and represents the internal dose of human exposure to VCM. The nanoprobe demonstrates high selectivity to TDGA with about 27.5-fold luminescence enhancement. It also displays excellent sensitivity with a detection limit as low as 89 ng·mL-1 and fast response to TDGA within 4 min, while refraining from the interference of other coexisting species in urine. Such good sensing performance enables the nanoprobe to practically monitor TDGA levels in human urine. Moreover, a portable urine dipstick based on the sensor is developed to conveniently evaluate individuals' intoxication degree of VCM. This fast, sensitive, and selective nanoprobe has promising potential to be a useful tool for point-of-care diagnosis of disease associated with VCM exposure.

A highly luminescent lanthanide-functionalized covalent organic framework for rapid and specific detection of 7-methylguanine for DNA methylation assessment.

Rapid and accurate detection of 7-methylguanine (m7Gua), a biomarker reflecting the degree of DNA methylation that occurs before or in the early stage of cancer, is of particular significance but remains a great challenge. Herein, a luminescent lanthanide-based covalent organic framework (Ln-COF) probe, namely DPA/Eu@ETTA-DHTA, is designed for the first time for the identification of m7Gua by assembling pyridine-2,6-dicarboxylic acid (DPA) as both an energy donor and a recognition molecule and Eu3+ ions as signal reporters into a stable COF matrix with high porosity and available binding sites. Significantly, the characteristic luminescence of Eu3+ ions can be turned on by the grafted DPA in the COF probe and effectively quenched by the addition of m7Gua via a competitive absorption process, thus achieving the sensing of m7Gua. Such a Ln-COF-based fluorescent platform presents high selectivity and a rapid response (<1 min) to m7Gua with a low detection limit (µM level) even in the presence of the main coexisting species in urine, allowing it to serve as a potentially practical probe for point-of-care monitoring of the level of m7Gua in human urine specimens. This study provides a convenient, time-saving, and economical approach for visual detection of m7Gua, and opens up new perspectives for the design of a luminescent COF-based probe for DNA methylation evaluation in diagnostics.

GSH-Responsive Organosilica Hybrid Nanosystem as a Cascade Promoter for Enhanced Starvation and Chemodynamic Therapy.

Glucose oxidase (GOD)-mediated starvation therapy (ST) that causes intratumoral glucose depletion is a promising strategy for tumor treatment. However, the ultimate efficacy is inevitably limited by tumor hypoxia, as oxygen is a key component in the consumption of glucose by GOD. In this study, a kind of glutathione (GSH)-responsive organosilica hybrid micelles loaded with Mn3 O4 and GOD (denoted as Mn3 O4 @PDOMs-GOD) is ingeniously designed for enhanced ST and chemodynamic therapy (CDT). Specifically, the internalized Mn3 O4 @PDOMs-GOD in tumor cells consumes intracellular glucose and oxygen (O2 ) under the catalysis of GOD to generate hydrogen peroxide (H2 O2 ), which is subsequently decomposed by Mn3 O4 to liberate O2 . This cyclically regenerated O2 will form a virtuous cycle of O2 and H2 O2 compensation to enhance the ST outcome. Meanwhile, Mn3 O4 can oxidize and deplete the overexpressed GSH in the tumor microenvironment (TME) to release Mn2+ , which then catalyzes H2 O2 into highly toxic hydroxyl radicals (·OH) to accomplish chemodynamic therapy (CDT). Both in vitro and in vivo experiment results demonstrate the significant antitumor efficacy of Mn3 O4 @PDOMs-GOD by the cooperatively enhanced ST and CDT, suggesting the feasibility to develop promising therapeutic platforms with higher treatment efficacies.

Dual "Unlocking" Strategy to Overcome Inefficient Nanomedicine Delivery and Tumor Hypoxia for Enhanced Photodynamic-Immunotherapy.

Lacking blood vessels is one of the main characteristics of most solid tumors due to their rapid and unrestricted growth, which thus causes the inefficient delivery efficiency of nanomedicine and tumor hypoxia. Herein, a dual "unlocking" strategy to overcome these obstacles is proposed by combining engineered hybrid nanoparticles (named ZnPc@FOM-Pt) with dexamethasone (DXM). It is verified that pretreatment of tumors with DXM can increase intratumorally micro-vessel density (delivery "unlocking") to enhance the tumor delivery efficiency of ZnPc@FOM-Pt and decrease HIF-1α expression. Correspondingly, more Pt can catalyze tumor-overexpressed H2 O2 to produce oxygen to further cause hypoxia "unlocking," ultimately achieving boosted ZnPc-based photodynamic therapy in vivo (tumor inhibition rate: 99.1%). Moreover, the immunosuppressive tumor microenvironment is efficiently reversed and the therapeutic effect of anti-PD-L1-based immunotherapy is promoted by this newly designed nanomedicine. This dual "unlocking" strategy provides an innovative paradigm on simultaneously enhancing nanomedicine delivery efficacy and hypoxia relief for tumor therapy.

Engineering of a NIR-activable hydrogel-coated mesoporous bioactive glass scaffold with dual-mode parathyroid hormone derivative release property for angiogenesis and bone regeneration.

Osteogenesis, osteoclastogenesis, and angiogenesis play crucial roles in bone regeneration. Parathyroid hormone (PTH), an FDA-approved drug with pro-osteogenic, pro-osteoclastogenic and proangiogenic capabilities, has been employed for clinical osteoporosis treatment through systemic intermittent administration. However, the successful application of PTH for local bone defect repair generally requires the incorporation and delivery by appropriate carriers. Though several scaffolds have been developed to deliver PTH, they suffer from the weaknesses such as uncontrollable PTH release, insufficient porous structure and low mechanical strength. Herein, a novel kind of NIR-activable scaffold (CBP/MBGS/PTHrP-2) with dual-mode PTHrP-2 (a PTH derivative) release capability is developed to synergistically promote osteogenesis and angiogenesis for high-efficacy bone regeneration, which is fabricated by integrating the PTHrP-2-loaded hierarchically mesoporous bioactive glass (MBG) into the N-hydroxymethylacrylamide-modified, photothermal agent-doped, poly(N-isopropylacrylamide)-based thermosensitive hydrogels through assembly process. Upon on/off NIR irradiation, the thermoresponsive hydrogel gating undergoes a reversible phase transition to allow the precise control of on-demand pulsatile and long-term slow release of PTHrP-2 from MBG mesopores. Such NIR-activated dual-mode delivery of PTHrP-2 by this scaffold enables a well-maintained PTHrP-2 concentration at the bone defect sites to continually stimulate vascularization and promote osteoblasts to facilitate and accelerate bone remodeling. In vivo experiments confirm the significant improvement of bone reparative effect on critical-size femoral defects of rats. This work paves an avenue for the development of novel dual-mode delivery systems for effective bone regeneration.

Engineered Organosilica Hybrid Micelles for Photothermal-enhanced Starvation Cancer Therapy.

Glucose oxidase (GOD)-based starvation therapy (ST), which inhibits the growth and proliferation of cancer cells by consuming glucose, has attracted intensive attention as an emerging non-invasive method for fighting cancers. However, the enzyme activity of GOD is greatly limited in vivo because of its optimal catalytic activity in the temperature range of 43-60 °C. Herein, a photothermal-enhanced starvation strategy is developed based on our engineered organosilica hybrid micelles (TiO2-x @POMs-GOD), in which the fluoride-doped TiO2-x with photothermal properties is encapsulated in the cores of organosilica cross-linked micelles and GOD is immobilized on the carboxyl groups of PAA segments. With its internalization by cancer cells, the conjugated GOD can effectively deplete glucose to achieve the ST effect, which can be remarkably enhanced by the loaded fluoride-doped TiO2-x with NIR laser irradiation, thus cooperatively contributing to the efficient treatment of TiO2-x @POMs-GOD on various cancer cells. This suggests great potential for TiO2-x @POMs-GOD in photothermal-enhanced ST in vivo.

One-pot fabrication of a polydopamine-based nanoplatform for GSH triggered trimodal ROS-amplification for cancer therapy.

Reactive oxygen species (ROS) based nanoplatforms have been considered as attractive and feasible candidates for cancer therapy. However, the activated endogenous antioxidant defense of cancer cells in response to the ROS attack greatly hinders their therapeutic efficacy. Although cancer-specific ROS amplification strategies have been widely explored, most of them suffer from tedious synthesis procedures and complex components, which will bring about undesired side effects and unsatisfactory results. Herein, we design a cancer-specific oxidative stress amplification nanomedicine (CA-Cu-PDA), which is simply fabricated through integrating the glutathione (GSH) responsive/depleting nanocarrier of copper-polydopamine (Cu-PDA) nanoparticles with a ROS-generating drug cinnamaldehyde (CA) via a facile one-pot polymerization route. It is verified that GSH could trigger the breakage of CA-Cu-PDA networks and the subsequent release of both copper ions and CA in cancer cells. The released copper ions efficiently oxidize GSH, thereby weakening the antioxidant system of cancer cells and increasing the ROS levels. On the other hand, extra ROS are generated by the reduced copper ions through a Fenton reaction, so that a synergistic ROS therapy with CA is achieved. Consequently, oxidative stress is specifically increased within cancer cells, leading to efficient cancer cell apoptosis, significant tumor suppression and minimized side effects. Such an ingenious structure realizes the interlocking cooperation and full utilization of each component's function, presenting promising perspectives for nanomedicine design.

A "Valve-Closing" Starvation Strategy for Amplification of Tumor-Specific Chemotherapy.

Starvation-dependent differential stress sensitization effect between normal and tumor cells provides a potentially promising strategy to amplify chemotherapy effects and reduce side effects. However, the conventional starvation approaches such as glucose oxidase (Gox)-induced glucose depletion and nanomedicine-enabled vascular embolism usually suffer from aggravated tumor hypoxia, systemic toxicity, and unpredictable metabolic syndrome. Herein, a novel "valve-closing" starvation strategy is developed to amplify the chemotherapy effects via closing the "valve" of glucose transported into tumor cells, which is accomplished by a glucose transporters 1 (GLUT1, valve of glucose uptake) inhibitor (Genistein, Gen) and chemotherapeutic agent (Curcumin, Cur) coloaded hybrid organosilica-micelles nanomedicine (designated as (Gen + Cur)@FOS) with controllable stability. In vitro and in vivo results demonstrate that (Gen + Cur)@FOS can effectively reduce glucose/adenosine triphosphate levels in tumor cells by inhibiting GLUT1 expression (i.e., "valve-closing") to induce the starvation of tumor cells, thus weakening the resistance of tumor cells to apoptosis caused by chemotherapy, and consequently contributing to the remarkably improved antitumor efficiency and minimized side effects based on the stress sensitization effect mediated by GLUT1 inhibition-induced starvation. This "valve-closing" starvation strategy provides a promising paradigm for the development of novel nanotherapeutics with amplified chemotherapy effect.

Multivalued Logic Assay of the Disease Marker of α-Ketoglutaric Acid by a Luminescent MOF-Based Biosensor.

α-Ketoglutaric acid (α-KA) is an important endogenous metabolite in the Krebs cycle and considered a critical marker for various diseases. Several approaches for identifying α-KA have been reported. However, most of them are limited to single-signal transduction modes in one assay and working in the suspension state, which easily cause quantification errors and lead to false-positive detection results. Herein, a multivalue-responsive and semi-solid EuMOF-gel (EuMOG) logic biosensor is first designed and fabricated, which can realize the specific, rapid, and easy-to-differentiate naked-eye detection of the disease-associated marker of α-KA in serum through implementing one-to-two logic operation with three multicolor gates. The implementation of one-to-two logic operation can be rationally achieved by assembling 2,6-naphthalenedicarboxylic acid as both the energy donor and blue-colored output 1, photoactive Eu3+ ions as the red-emissive output 2, and α-KA stimuli as an input and energy blocker between the dual spectrum-resolved outputs into one unit. With the specific input of α-KA among various analytes, the binary code of the logic decoder switches from (0,1) to (1,0) with an obvious color change from red to cyan. Moreover, by integrating the output chromaticity into the logical operations, the concentration levels of α-KA could be easily evaluated with the intelligent EuMOG detector, which has three multicolor gates in parallel encoding low (0,1), normal (1,1), and danger (1,0) statuses. Such multivalued logic biosensor provides a facile strategy to improve the analysis reliability of disease-associated biomarkers.

Structure Engineering of a Lanthanide-Based Metal-Organic Framework for the Regulation of Dynamic Ranges and Sensitivities for Pheochromocytoma Diagnosis.

Exploring innovative technologies to precisely quantify biomolecules is crucial but remains a great challenge for disease diagnosis. Unfortunately, the humoral concentrations of most biotargets generally vary within rather limited scopes between normal and pathological states, while most literature-reported biosensors can detect large spans of targets concentrations, but are less sensitive to small concentration changes, which consequently make them mostly unsatisfactory or even unreliable in distinguishing positives from negatives. Herein, a novel strategy of precisely quantifying the small concentration changes of a certain biotarget by editing the dynamic ranges and sensitivities of a lanthanide-based metal-organic framework (Eu-ZnMOF) biosensor is reported. By elaborately tailoring the biosensor's structure and surface areas, the tunable Eu-ZnMOF is developed with remarkably enhanced response slope within the "optimized useful detection window," enabling it to serve as a powerful signal amplifier (87.2-fold increase) for discriminating the small concentration variation of urinary vanillylmandelic acid (an early pathological signature of pheochromocytoma) within only three times between healthy and diseased subjects. This study provides a facile approach to edit the biosensors' performances through structure engineering, and exhibits promising perspectives for future clinical application in the non-invasive and accurate diagnosis of severe diseases.

A Double-Stimuli-Responsive Fluorescent Center for Monitoring of Food Spoilage based on Dye Covalently Modified EuMOFs: From Sensory Hydrogels to Logic Devices.

Unsafe food is a huge threat to human health and the economy, and detecting food spoilage early is an ongoing and imperative need. Herein, a simple and effective strategy combining a fluorescence sensor and one-to-two logic operation is designed for monitoring biogenic amines, indicators of food spoilage. Sensors (methyl red@lanthanide metal-organic frameworks (MR@EuMOFs)) are created by covalently modifying MR into NH2 -rich EuMOFs, which have a high quantum yield (48%). A double-stimuli-responsive fluorescence center is produced via energy transfer from the ligands to Eu3+ and MR. Portable sensory hydrogels are obtained by dispersing and solidifying MR@EuMOFs in water-phase sodium salt of carboxy methyl cellulose (CMC-Na). The hydrogels exhibit a color transition upon "smelling" histamine (HI) vapor. This transition and shift in the MR-based emission peak are closely related to the HI concentration. Using the HI concentration as the input signal and the two fluorescence emissions as output signals, an advanced analytical device based on a one-to-two logic gate is constructed. The four output combinations, NOT (0, 1), YES (1, 0), PASS 1 (1, 1), and PASS 0 (0, 0), allow the direct analysis of HI levels, which can be used for real-time food-freshness evaluation. The novel strategy suggested here may be a new application for a molecular logic system in the sensing field.

A dual-emitting 4d-4f nanocrystalline metal-organic framework as a self-calibrating luminescent sensor for indoor formaldehyde pollution.

A dual-emissive 4d-4f Ag(i)-Eu(iii) functionalized MOF nanocomposite was fabricated and utilized as a self-calibrating luminescent nanoprobe for detecting indoor formaldehyde (FA). The implantation of Ag(+) ions can tune the dual-emissive characters of the material. FA can interact with the Ag(+) ions and induce opposite luminescence behaviors of the two emitters in the singular molecular material, thus realizing its recognition. This nanoprobe for FA exhibits many merits, such as excellent selectivity, high sensitivity with a detection limit of 51 ppb, fast response, room-temperature testing ability, easy preparation and low cost. This is the first example of a MOF-implicated self-calibrated sensor for indoor FA detection.

Simultaneous determination of indoor ammonia pollution and its biological metabolite in the human body with a recyclable nanocrystalline lanthanide-functionalized MOF.

A Eu(3+) post-functionalized metal-organic framework of nanosized Ga(OH)bpydc(Eu(3+)@Ga(OH)bpydc, 1a) with intense luminescence is synthesized and characterized. Luminescence measurements reveal that 1a can detect ammonia gas selectively and sensitively among various indoor air pollutants. 1a can simultaneously determine a biological ammonia metabolite (urinary urea) in the human body, which is a rare example of a luminescent sensor that can monitor pollutants in the environment and also detect their biological markers. Furthermore, 1a exhibits appealing features including high selectivity and sensitivity, fast response, simple and quick regeneration, and excellent recyclability.

A water-stable lanthanide-functionalized MOF as a highly selective and sensitive fluorescent probe for Cd(2.).

A highly selective and sensitive fluorescent sensor for Cd(2+) in aqueous solution based on a lanthanide post-functionalized metal-organic framework was developed.

Recyclable lanthanide-functionalized MOF hybrids to determine hippuric acid in urine as a biological index of toluene exposure.

A lanthanide-functionalized MOF with extremely high water tolerance was developed as a fluorescent probe for hippuric acid (HA) in urine which is considered as the biological indicators of toluene exposure. For the first time, the urinary HA was detected by fluorescence spectrometry based on a recyclable Ln-MOF sensor.

Photofunctional host-guest hybrid materials and thin films of lanthanide complexes covalently linked to functionalized zeolite A.

Eight host-guest assemblies of zeolite A (ZA) and their thin films have been synthesized. The assembly of zeolite A was prepared by first embedding lanthanide complexes (Eu(TTA)n or Tb(TAA)n) into the cages of zeolite A and then grafting lanthanide complexes (Eu(L) or Tb(L), L = bipy or phen) onto the surface of functionalized zeolite A via 3-(methacryloyloxy)propyltrimethoxysilane (γ-MPS). The obtained organic-inorganic hybrid materials were investigated by means of XRD, FT-IR, SEM and luminescence spectroscopy. Firstly, the dependence of the crystal stability of zeolite A as the host of lanthanide complexes on the level of ion exchange was studied by XRD. The results indicated the degradation and partial collapse of zeolite A framework occurred upon doping with high amounts of lanthanide complexes into its channels. The integrity of zeolite A's framework was well maintained after fabrication through careful control of the ion-exchange extent. Secondly, the thin films of zeolite A assemblies obtained this way have the properties of homogeneous dense packing and a high degree of coverage of the crystals on the ITO glass, as shown in SEM images. Thirdly, the luminescence behavior of all the materials were investigated in detail. Among them, four white light-emitting materials from a three-component system that comprises a blue-emitting zeolite A matrix, a red-emitting europium complex and a green-emitting terbium complex were obtained.