Copper-Coordinated Covalent Organic Framework Produced a Robust Fenton-Like Effect Inducing Immunogenic Cell Death of Tumors.

Increasing infiltration of CD8+ T cells can enhance the response rate to immune checkpoint blockade (ICB) therapies. In contrast, immunogenic cell death (ICD) induced by intracellular reactive oxygen species (ROS) is an effective strategy to increase CD8+ T cell infiltration. Cuproptosis is newly defined and reported by Tsvetkov et al. A Cu-coordinated covalent organic framework (COF) in which two valence states of copper ions are simultaneously loaded is prepared. On the one hand, Cu2+ undergoes a valence shift generating Cu+ which acts as an effective Fenton-like reagent to catalyze the production of · OH and 1 O2 from cellular overexpressed H2 O2 , causing DNA damage and lipid peroxidation (LPO), which directly produce cytotoxicity. On the other hand, residual Cu2+ can effectively deplete endogenous cellular glutathione (GSH), converting it into glutathione disulfide (GSSG), further increasing intracellular oxidative stress and reducing the scavenging of ROS, thus further enhancing the Fenton-like effect and bringing toxic effects on tumor cells. The synergy of these two functions achieves ICD, helping for transforming "cold tumor" into "hot tumor" and efficient anti-tumor effects eventually. This work provides new insights into coordinated COF and inspire the development of more versatile COF for biomedical applications.

A Two-In-One Nanoprodrug for Photoacoustic Imaging-Guided Enhanced Sonodynamic Therapy.

Sonodynamic therapy (SDT) is garnering considerable attention in cancer treatment due to its non-invasive nature and the potential of spatiotemporal control. However, the high level of glutathione (GSH) in cancer cells can alleviate the SDT-mediated ROS-damages, resulting in a reduced SDT effect. Here, a two-in-one nano-prodrug for photoacoustic imaging-guided enhanced SDT against skin cancers is synthesized. A dual-prodrug molecule (DOA) of sulfide dioxide (SO2 ) and 5-aminolevulinic acid (ALA) is first synthesized and then co-assembled with methoxyl poly(ethylene glycol)-b-poly(l-lysine) (mPEG-b-PLL) to generate the two-in-one prodrug nanoparticles (P-DOA NPs). The P-DOA NPs simultaneously released ALA and SO2 in response to the overexpressed GSH in tumor cells. The released ALA is metabolically converted into protoporphyrin IX (PpIX) in tumor cells for SDT and photoacoustic imaging. Meanwhile, the released SO2 , together with the consumption of GSH based on the reaction of DOA in P-DOA NPs with intracellular GSH, can significantly increase the intracellular ROS content, leading to enhanced SDT. As a result, the P-DOA NPs significantly inhibited the growth of melanoma and squamous cell carcinoma xenografts in mouse models under the guidance of real-time photoacoustic imaging. Therefore, this novel two-in-one nano-prodrug is promising for effective SDT against skin cancers.

psoResNet: An improved PSO-based residual network search algorithm.

Neural Architecture Search (NAS) methods are widely employed to address the time-consuming and costly challenges associated with manual operation and design of deep convolutional neural networks (DCNNs). Nonetheless, prevailing methods still encounter several pressing obstacles, including limited network architecture design, excessively lengthy search periods, and insufficient utilization of the search space. In light of these concerns, this study proposes an optimization strategy for residual networks that leverages an enhanced Particle swarm optimization algorithm. Primarily, low-complexity residual architecture block is employed as the foundational unit for architecture exploration, facilitating a more diverse investigation into network architectures while minimizing parameters. Additionally, we employ a depth initialization strategy to confine the search space within a reasonable range, thereby mitigating unnecessary particle exploration. Lastly, we present a novel approach for computing particle differences and updating velocity mechanisms to enhance the exploration of updated trajectories. This method significantly contributes to the improved utilization of the search space and the augmentation of particle diversity. Moreover, we constructed a crime-dataset comprising 13 classes to assess the effectiveness of the proposed algorithm. Experimental results demonstrate that our algorithm can design lightweight networks with superior classification performance on both benchmark datasets and the crime-dataset.

Biodegradable covalent organic frameworks achieving tumor micro-environment responsive drug release and antitumor treatment.

The emergence of nanocarriers has greatly improved the therapeutic efficacy of chemotherapeutic drugs. As emerging nanocarriers, covalent organic frameworks (COFs) have been increasingly used in biomedicine in recent years. However, due to their inherent chemical stability, existing COF nanocarriers hardly undergo in vivo degradation, which brings potential safety hazards to further applications. In this work, we introduce the azo bond into COFs. When the nanocarrier enters the cell, ˙OH generated by the coordinated Fe response to the H2O2 in the cell will break the azo bond and cause the degradation of the framework structure, accelerating the release of internally loaded DOX to effectively realize tumor treatment. We verified the degradation ability of the materials by constructing model compounds, in vitro drug release, MTT assay and antitumor experiments. Compared with the control groups, the degradable COF accelerates the release of DOX and shows a stronger killing effect on 4T1 cells. Serum biochemical analysis and H&E sections of organs show good biocompatibility for both COFs and degradation products. This work provides a new idea for the design of biodegradable COFs in vivo, and greatly explores the potential application of COF materials in the biomedical field.

A Multifunctional Nanoparticle Mitigating Cytokine Storm by Scavenging Multiple Inflammatory Mediators of Sepsis.

Sepsis is a disease caused by infection, which is characterized by a dysregulated immune response in the host and affects more than 30 million people worldwide each year. However, the current single therapeutic approaches are not effective in controlling the progression of sepsis. Here, we synthesize a nanoparticle (TMP) containing tannic acid (TA), Polymyxin B (PMB), and Mn2+ (Mn) by a simple one-pot method. TMP has the following characteristics: (1) All components have good biocompatibility; (2) simple preparation process without subsequent processing; (3) antibacterial and remove multiple inflammatory mediators; and (4) effectively mitigating cytokine storm both in the acute lung injury (ALI) and the cecal ligation and puncture (CLP) model. Our results demonstrate the critical role of targeting multiple mediators to mitigate cytokine storms for the treatment of sepsis.

Enhancing the drug sensitivity of antibiotics on drug-resistant bacteria via the photothermal effect of FeTGNPs.

The growing problem of bacterial resistance caused by the abuse of antibiotics is a serious challenge for the world. In order to make the clinically available antibiotics regain their bactericidal effect, our study introduced photothermal therapy (PTT) to assist antibiotics to annihilate drug-resistant bacteria. To achieve the synergistic effect, nanoparticles (FeTGNPs) with an antibiotic core (gatifloxacin complexing with tannins) and a photothermal shell (ferric iron coordinating with tannins) were prepared directly in aqueous solution by a convenient yet efficient one-pot synthesis. The excellent photothermal properties of the shell of FeTGNPs were used to break the mechanism of bacterial resistance, and the sustained-release of gatifloxacin from the core regained the killing effect against drug-resistant bacteria. From the results of antibacterial experiments, with the synergistic effect of APTT and antibiotics, FeTGNPs (400 µg/mL) could effectively kill methicillin-resistant Staphylococcus aureus (sterilizing rate up to 96.5 %) and gatifloxacin-resistant Staphylococcus aureus (sterilizing rate up to 98.7 %) than equivalent antibiotics. Moreover, under slightly acidic microenvironment, such as infection area, gatifloxacin could accelerate its release from the core of FeTGNPs. Therefore, FeTGNPs would be a highly effective antibacterial agent against drug-resistant bacterial infections in the future.

Etching Bulk Covalent Organic Frameworks into Nanoparticles of Uniform and Controllable Size by the Molecular Exchange Etching Method for Sonodynamic and Immune Combination Antitumor Therapy.

To improve the therapeutic effect of sonodynamic therapy (SDT), more effective and stable sonosensitizers and therapeutic strategies are still required. A covalent organic framework (COF) sonosensitizer is developed by using a new nanoscale COF preparation strategy. This strategy uses molecular etching based on the imine exchange reaction to etch the bulk COF into nanoparticles and has universal applicability to imine-bond-based COF. The regular COF structure can prevent the loss of sonodynamic performance caused by the aggregation of porphyrin molecules and improve the chemical stability of the porphyrin unit. In addition, the coordination of Fe3+ to COF endows the nanoparticle with chemodynamic therapy performance and glutathione consumption ability. The combination of enhanced SDT and α-PD-L1 antibody achieves a good antitumor effect. The innovative nanoscale COF sonosensitizer preparation strategy provides a new avenue for clinical antitumor therapy.

A High Visibility and SNR Image From One Single-Shot Low-Light Image.

Achieving high visibility and high signal-to-noise ratio (SNR) from a single-shot image captured in low-light environments is an under-constrained problem. To cope with this issue, the intrinsic relationship between the image domain and the radiance domain is first established based on the human visual model, the atmospheric scattering model, and the camera imaging model, and the ideal exposure is derived. Using the illumination-reflection-noise prior, a new convex optimization by employed gradient constraint and the Krisch operator is then presented to estimate the noise-reduced illumination and reflection components. A high SNR image in the optimal exposure is generated in radiance domain, which is finally inversely mapped to obtain a high SNR image in image domain. Experimental results in subjective and objective tests show that the proposed algorithm has a high SNR and pleasant perception in comparison with the state-of-the-art methods.

Fe-TCPP@CS nanoparticles as photodynamic and photothermal agents for efficient antimicrobial therapy.

Traditional antimicrobial therapies always rely on antibiotics, which have led to the overuse of antibiotics and caused the emergence of multidrug-resistant (MDR) bacteria in recent years. In this study, an efficient and broad-spectrum antimicrobial system based on chitosan (CS)-encapsulated multifunctional metal-organic nanoparticles (Fe-TCPP@CS NPs) was constructed to integrate the electrostatic targeting property and photodynamic and photothermal antimicrobial therapies. Tetrakis (4-carboxyphenyl) porphyrin (TCPP) coordinated with Fe3O clusters to form nanoparticles, Fe3O clusters enabled low-temperature photothermal therapy as well as avoiding the porphyrins self-aggregation to ensure the singlet oxygen yield under irradiation, and CS as the outer layer covered on Fe-TCPP nanoparticles could improve the dispersibility in aqueous solution and enhance the electrostatic binding with bacterial cell membranes to improve the antibacterial activities. After simple synthesis, we successfully obtained ideal and biocompatible multifunctional nanoparticles and verified their antimicrobial properties. Under light irradiation, Fe-TCPP@CS NPs could produce enough ROS and heat to kill S. aureus, E. coli and methicillin-resistant S. aureus with a synergistic effect. Therefore, Fe-TCPP@CS NPs would be an efficient and broad-spectrum antimicrobial agent, providing a novel approach to bacterial infection therapy.

A glutathione-depleting chemodynamic therapy agent with photothermal and photoacoustic properties for tumor theranostics.

Nowadays, Fenton reaction-based chemodynamic therapy (CDT) strategies have drawn extensive attention as tumor-specific nanomedicine-based therapy. Nevertheless, current existing CDTs normally suffer from therapeutic bottlenecks such as the scavenging of hydroxyl radical (˙OH) by intracellular antioxidants and unideal therapeutic outcome of single treatment modality. Herein, we constructed novel all-in-one AFP nanoparticles (NPs) as CDT agents through a one-pot process for multifunctional nanotheranostics. The as-constructed AFP NPs could simultaneously produce ˙OH through the Fenton reaction and scavenge intracellular glutathione, functioning as self-reinforced CDT agents to achieve tumor-triggered enhanced CDT (ECDT). In addition, the AFP NPs possessed the capability of H2O2 and acid-boosted photoacoustic imaging and photothermal therapy, enabling a precise and effective tumor therapeutic outcome with minimal nonspecific damage in combination with ECDT. Our novel nanoplatform would open new perspectives on multi-functional CDT agents for accurate and non-invasive tumor theranostics.

Helix Self-Assembly Behavior of Amino Acid-Modified Camptothecin Prodrugs and Its Antitumor Effect.

For effective antitumor treatment, it is important to increase the water solubility of hydrophobic antitumor drugs and improve their cell absorption efficiency and nuclear transmission capacity. Here, we use endogenous hydrophilic arginine to modify camptothecin (CPT) to increase its water solubility. Surprisingly, the modified CPT can self-assemble into helical nanofibers through intermolecular π-π stacking and hydrophilic-hydrophobic interactions. Prodrug-based nanofibers were better endocytosed into the nucleus than their nonassembled CPT. Moreover, in vivo, such nanofibers had a longer blood circulation time and a better ability to accumulate in the tumor site. Further, we found that the cationic nanofibers can be combined with the anionic cisplatin-polyglutamic acid through electrostatic interaction to achieve a combined antitumor effect. This provides a new idea for achieving more effective cancer chemotherapy effects.

MiR-155-5p accelerates the metastasis of cervical cancer cell via targeting TP53INP1.

Background: The dysregulation of microRNAs has been implicated in the progression of different malignancies. Herein, we sought to identify the precise roles of miR-155-5p in the progression of cervical cancer. Materials and methods: The expressions of miR-155-5p in cervical carcinoma cells and clinical tissues were assessed using qRT-PCR analysis. The functions of miR-155-5p on the growth of cervical cancer cell were investigated using MTT and colony formation. The Transwell and wound closure assays were selected to explore the influence of miR-155-5p on the invasion and migration of cervical cancer cell. The effect of miR-155-5p on cervical carcinoma cell growth and metastasis in vivo was investigated using xenograft model and experimental lung metastasis model. Bioinformatics analysis and luciferase reporter assay were applied to identify that tumor protein p53-inducible nuclear protein 1 (TP53INP1) was the target of miR-155-5p. Results: MiR-155-5p was significantly upregulated in cervical cancer tissue than that in control normal tissue. Downexpression of miR-155-5p decreased the growth, migration as well as invasiveness abilities of cervical cancer cell in vitro whereas overregulation of miR-155-5p caused the opposite outcomes. In addition, the in vivo mice xenograft model suggested that downexpression of miR-155-5p restrained the progression of cervical cancer cell whereas overexpression of miR-155-5p caused opposite outcomes. Furthermore, we revealed that TP53INP1 was the target of miR-155-5p and the level of TP53INP1 was inversely associated with miR-155-5p level in cervical carcinoma. Furthermore, TP53INP1 knockdown mimicked the influence of miR-155-5p on cervical cancer proliferation, migration and invasion phenotypes. Finally, overexpression of TP53INP1 impaired the promote effect of miR-155-5p on cervical cancer cell and downregulation of TP53INP1 counteracted the suppressive impact of miR-155-5p on the aggressiveness of cervical cancer cell. Conclusion: Our study indicated that miR-155-5p regulated the development of cervical cancer cell by regulating the expression of TP53INP1.

Porphyrin-based covalent organic framework nanoparticles for photoacoustic imaging-guided photodynamic and photothermal combination cancer therapy.

Combination of photodynamic therapy (PDT) and photothermal therapy (PTT) generally requires different components to build a composite irradiated with different excitation lights. One component photoactive agent for enhanced combination of PDT and PTT under the excitation of a single wavelength light source is more urgent in tumor phototherapy via adjusting spatial arrangement of photoactive units. Herein, porphyrin-based covalent organic framework nanoparticles (COF-366 NPs) were synthesized to control the orderly spatial arrangement of the photoactive building units and firstly used for antitumor therapy in vivo. COF-366 NPs provide the simultaneous therapy of PDT and PTT under a single wavelength light source with the monitoring of photoacoustic (PA) imaging, which makes the operation simpler and more convenient. COF-366 NPs had achieved good phototherapy effect even in the face of large tumors. The prepared multifunctional COF-366 NPs open up a new avenue to phototherapeutic materials and expand the application range of covalent organic framework.