GSH-Responsive Metal-Organic Framework for Intratumoral Release of NO and IDO Inhibitor to Enhance Antitumor Immunotherapy.

Immunotherapy brings great benefits for tumor therapy in clinical treatments but encounters the severe challenge of low response rate mainly because of the immunosuppressive tumor microenvironment. Multifunctional nanoplatforms integrating effective drug delivery and medical imaging offer tremendous potential for cancer treatment, which may play a critical role in combinational immunotherapy to overcome the immunosuppressive microenvironment for efficient tumor therapy. Here, a nanodrug (BMS-SNAP-MOF) is prepared using glutathione (GSH)-sensitive metal-organic framework (MOF) to encapsulate an immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) inhibitor BMS-986205, and the nitric oxide (NO) donor s-nitrosothiol groups. The high T1 relaxivity allows magnetic resonance imaging to monitor nanodrug distribution in vivo. After the nanodrug accumulation in tumor tissue via the EPR effect and subsequent internalization into tumor cells, the enriched GSH therein triggers cascade reactions with MOF, which disassembles the nanodrug to rapidly release the IDO-inhibitory BMS-986205 and produces abundant NO. Consequently, the IDO inhibitor and NO synergistically modulate the immunosuppressive tumor microenvironment with increase CD8+ T cells and reduce Treg cells to result in highly effective immunotherapy. In an animal study, treatment using this theranostic nanodrug achieves obvious regressions of both primary and distant 4T1 tumors, highlighting its application potential in advanced tumor immunotherapy.

Redox Responsive Metal Organic Framework Nanoparticles Induces Ferroptosis for Cancer Therapy.

Ferroptosis is attracting significant attention due to its effectiveness in tumor treatment. The efficiency to produce toxic lipid peroxides (LPOs) at the tumor site plays a key role in ferroptosis. A hybrid PFP@Fe/Cu-SS metal organic framework (MOF) is synthesized and shown to increase intratumoral LPO content through redox reactions generating ·OH. In addition, glutathione (GSH) depletion through disulfide-thiol exchange leads to the inactivation of glutathione peroxide 4 (GPX4), which results in a further increase in LPO content. This MOF exhibits high inhibitory effect on the growth of xenografted Huh-7 tumors in mice. The coadministration of a ferroptosis inhibitor reduces the antitumor effect of the MOF, leading to a restoration of GPX4 activity and an increase in tumor growth. Moreover, the construction of Cu into mesoporous PFP@Fe/Cu-SS not only allows the MOF to be used as a contrast agent for T1 -weighted magnetic resonance imaging, but also renders its photothermal conversion capacity. Thus, near-infrared irradiation is able to induce photothermal therapy and transform the encapsulated liquid perfluoropentane into microbubbles for ultrasound imaging.

State dependence of CO2 forcing and its implications for climate sensitivity.

When evaluating the effect of carbon dioxide (CO2) changes on Earth's climate, it is widely assumed that instantaneous radiative forcing from a doubling of a given CO2 concentration (IRF2×CO2) is constant and that variances in climate sensitivity arise from differences in radiative feedbacks or dependence of these feedbacks on the climatological base state. Here, we show that the IRF2×CO2 is not constant, but rather depends on the climatological base state, increasing by about 25% for every doubling of CO2, and has increased by about 10% since the preindustrial era primarily due to the cooling within the upper stratosphere, implying a proportionate increase in climate sensitivity. This base-state dependence also explains about half of the intermodel spread in IRF2×CO2, a problem that has persisted among climate models for nearly three decades.

Triple Tumor Microenvironment-Responsive Ferroptosis Pathways Induced by Manganese-Based Imageable Nanoenzymes for Enhanced Breast Cancer Theranostics.

Previous studies have found that activated CD8+ T cells secrete elevated levels of interferon-gamma (IFN-γ) to trigger ferroptosis in tumor cells. However, IFN-γ-mediated ferroptosis is induced at low levels in tumor cells because of the limited IFN-γ secreted by CD8+ T cells in the immunosuppressive tumor microenvironment. Recent studies have shown that manganese ion can activate the cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase/stimulator of interferon genes (cGAS-STING) pathway and support adaptive immune responses against tumors, which enhances the level of tumor-infiltrating CD8+ T cells. Therefore, tumor microenvironment-responsive Mn-based nanoenzymes (Mn-based NEs) that activated the cGAS-STING pathway are designed to amplify immune-driven ferroptosis. The multifunctional all-in-one nanoplatform is simply and mildly synthesized by the coordination between Mn3+ ions and 3,3'-dithiodipropionic acid. After intracellular delivery, each component of Mn-based NEs exerts its function. That is, glutathione is depleted through disulfide-thiol exchange and redox pair of Mn3+ /Mn2+ , a hydroxyl radical (·OH) is generated via the Fenton-like reaction to cause ferroptosis, and Mn2+ augments cGAS-STING activity to boost immune-driven ferroptosis. In addition, ferroptosis amplifies Mn2+ -induced immunogenic cell death and initiates the antitumor immune "closed loop" along with immune-driven ferroptosis. Notably, this multifunctional nanoplatform is effective in killing both primary and distant tumors.

Precise synthesis and photovoltaic properties of giant molecule acceptors.

Series of giant molecule acceptors DY, TY and QY with two, three and four small molecule acceptor subunits are synthesized by a stepwise synthetic method and used for systematically investigating the influence of subunit numbers on the structure-property relationship from small molecule acceptor YDT to giant molecule acceptors and to polymerized small molecule acceptor PY-IT. Among these acceptors-based devices, the TY-based film shows proper donor/acceptor phase separation, higher charge transfer state yield and longer charge transfer state lifetime. Combining with the highest electron mobility, more efficient exciton dissociation and lower charge carrier recombination properties, the TY-based device exhibits the highest power conversion efficiency of 16.32%. These results indicate that the subunit number in these acceptors has significant influence on their photovoltaic properties. This stepwise synthetic method of giant molecule acceptors will be beneficial to diversify their structures and promote their applications in high-efficiency and stable organic solar cells.

Programmable therapeutic nanoscale covalent organic framework for photodynamic therapy and hypoxia-activated cascade chemotherapy.

Clinical photodynamic therapy (PDT) only has a limited cancer therapeutic effect and typically leads to a more hypoxic milieu owing to the hypoxic conditions of the solid tumor microenvironment that limit the singlet oxygen (1O2), generation. To address this issue, the PDT, in combination with hypoxia-activated prodrugs, has recently been investigated as a possible clinical treatment modality for cancer therapy. By cross-linking the photosensitizer tetra(4-hydroxyphenyl)porphine (THPP) and a 1O2-cleavable thioketal (TK) linker, a multifunctional nanoscale covalent organic framework (COF) platform with a high porphyrin loading capacity was synthesized, which significantly improve the reactive oxygen species (ROS) generation efficiency and contributes to PDT. As-synthesized THPPTK-PEG nanoparticles (NPs) possess a high THPP photosensitizer content and mesoporous structure for further loading of the hypoxia-responsive prodrug banoxantrone (AQ4N) into the COF with a high-loading content. The nano-carriers surfaces are coated with a thick PEG coating to promote their dispersibility in physiological surroundings and therapeutic performance. When exposed to 660 nm radiation, such a nanoplatform can efficiently create cytotoxic 1O2 for PDT. Similarly, oxygen intake may exacerbate the hypoxic environment of the tumor, inducing the activation of AQ4N to achieve hypoxia-activated cascade chemotherapy and increased treatment efficacy. This study provides a new nanoplatform for photodynamic-chemical synergistic therapy and offers critical new insights for designing and developing a multifunctional supramolecular drug delivery system. STATEMENT OF SIGNIFICANCE: Here, we designed a laser-activated hypoxia-responsive nanoscale COF nanoplatform for hypoxia-activated cascade chemotherapy and PDT. When exposed to laser light, thus this nanoplatform can efficiently create cytotoxic 1O2 for PDT while consuming oxygen at the tumor location. However, increased oxygen consumption can exacerbate the tumor's hypoxic environment, causing AQ4N to become active, allowing for programmed hypoxia-triggered cascade chemotherapy and improved therapeutic efficacy. In addition, this innovative nanoscale COF nanoplatform allows for laser-controlled drug delivery in specific areas, which dramatically improves tumor inhibition. This research suggests a method for attaining ultrasensitive drug release and effective cascade therapy for cancer treatments.

Molecular imaging nanoprobes for theranostic applications.

As a non-invasive imaging monitoring method, molecular imaging can provide the location and expression level of disease signature biomolecules in vivo, leading to early diagnosis of relevant diseases, improved treatment strategies, and accurate assessment of treating efficacy. In recent years, a variety of nanosized imaging probes have been developed and intensively investigated in fundamental/translational research and clinical practice. Meanwhile, as an interdisciplinary discipline, this field combines many subjects of chemistry, medicine, biology, radiology, and material science, etc. The successful molecular imaging not only requires advanced imaging equipment, but also the synthesis of efficient imaging probes. However, limited summary has been reported for recent advances of nanoprobes. In this paper, we summarized the recent progress of three common and main types of nanosized molecular imaging probes, including ultrasound (US) imaging nanoprobes, magnetic resonance imaging (MRI) nanoprobes, and computed tomography (CT) imaging nanoprobes. The applications of molecular imaging nanoprobes were discussed in details. Finally, we provided an outlook on the development of next generation molecular imaging nanoprobes.

A photo and tumor microenvironment activated nano-enzyme with enhanced ROS generation and hypoxia relief for efficient cancer therapy.

Reactive oxygen species (ROS) mediated tumor therapy strategies have exhibited great prospects and attracted increasing attention, among which photodynamic therapy (PDT) has been well-established. However, the anticancer effects of PDT are greatly limited by the hypoxic tumor microenvironment (TME). Hence, exploring a therapeutic strategy that can relieve tumor hypoxia is regarded as the key to overcoming this problem. Herein, we develop a novel nano-enzyme (MnO2@TPP-PEG) that can accurately conduct tumor-specific catalysis of H2O2 to produce oxygen through a Fenton-like reaction, leading to an enhanced PDT under the irradiation of light. More importantly, the process of catalyzing H2O2 decomposition at the tumor location can also generate a cytotoxic hydroxyl radical (˙OH), achieving an excellent chemodynamic therapy (CDT) to enhance the ROS mediated anti-cancer effect. Notably, the nano-enzyme exerts a high loading content of the photosensitizer, which minimizes the side effects probably caused by the vector.

One-/Two-Photon Excited Cell Membrane Imaging and Tracking by a Photoactive Nanocage.

Cell membrane imaging by predesigned molecular and supramolecular photoluminescence probes is of great importance in understanding the nano-biointeractions for potential applications in cellular tracking, drug delivery, cancer diagnosis, and treatment. Herein, we report an effective strategy for cell membrane imaging in both living cell and tissue levels on the basis of a multifunctional nanocage (MOC-16) integrating one-/two-photon active phosphorescence, high charges, balanced hydrophobicity/lipophilicity, and proton sensitivity attributes. The intrinsic optical characters, including strong one-/two-photon excitation and pH-dependent red emission, make MOC-16 powerful optical probes for membrane imaging in living cell and tissue levels under both visible and near-infrared irradiations. Meanwhile, the highly positive charges of +28 endow MOC-16 with adequate water solubility and deprotonation ability while still maintaining its hydrophobicity, thus enabling balanced hydrophobic-lipophilic interactions at the nano-biointerface to facilitate a pH-dependent membrane absorption within the biological pH range of 5.3-7.4. However, the low-charged RuL3 metalloligand or polyethylene glycol (PEG)-modified MOC-16PEG with less hydrophobicity cannot offer enough nano-biointeractions for cell membrane tracking. These findings advance the fundamental understanding of nano-biointerface interactions of MOCs with cell membranes and provide further guidance in their biological applications.

Near-Infrared-Light-Induced Morphology Transition of Poly(ether amine) Nanoparticles for Supersensitive Drug Release.

Near-infrared (NIR)-light-controlled drug release has aroused great interest because of its advantages in spatiotemporal control. Herein, a photothermally induced morphology transition of the nanoparticles (NPs) for supersensitive drug release has been demonstrated. Doxorubicin (DOX)- and cyanine (Cy)-coloaded thermosensitive poly(ether amine) NPs (DOX&Cy@PEA81) were developed. Because of the photothermal activity of Cy upon irradiation, increase in temperature at the tumor site results, which would be used not only for photothermal therapy but also to spur the release of DOX from the NPs for tunable chemotherapy. The NIR-laser-driven DOX release was validated by a series of intracellular and in vivo experiments on animals. Meanwhile, the chemo-photothermal combinatorial therapy results in optimal cytotoxicity and tumor inhibition. This article provides a promising approach to realizing supersensitive drug release and synergistic chemo-photothermal therapy for cancer.

Diketopyrrolopyrrole-based carbon dots for photodynamic therapy.

The development of a simple and straightforward strategy to synthesize multifunctional carbon dots for photodynamic therapy (PDT) has been an emerging focus. In this work, diketopyrrolopyrrole-based fluorescent carbon dots (DPP CDs) were designed and synthesized through a facile one-pot hydrothermal method by using diketopyrrolopyrrole (DPP) and chitosan (CTS) as raw materials. DPP CDs not only maintained the ability of DPP to generate singlet oxygen (1O2) but also have excellent hydrophilic properties and outstanding biocompatibility. In vitro and in vivo experiments demonstrated that DPP CDs greatly inhibited the growth of tumor cells under laser irradiation (540 nm). This study highlights the potential of the rational design of CDs for efficient cancer therapy.

Photothermally induced accumulation and retention of polymeric nanoparticles in tumors for long-term fluorescence imaging.

The development of long-term tumor imaging is of great importance for effective theranostic systems. In this study, a temperature-responsive poly(ether amine) with a phase transition temperature around 43 °C was used to encapsulate indocyanine green (ICG), which is a near infrared fluorescent and photothermal agent. Upon photothermal treatment, the polymeric nanoparticles underwent an increase in size from the nano- to the microscale. The prepared ICG-loaded PEAs exhibited significant stability against photobleaching and excellent NIR imaging ability. The increase in particle size resulted in the accumulation and retention of nanoparticles at the tumor site upon photothermal treatment. The accumulation of nanoparticles facilitated long-term imaging of the tumor for up to 30 days after one injection. This study highlights the potential of the rational design of polymer nanoparticles for bioimaging and diagnostics.