Neuropilin-1-Targeted Nanomedicine for Spatiotemporal Tumor Suppression through Photodynamic Vascular Damage and Antiangiogenesis.

Antiangiogenic therapy is an effective way to disrupt nutrient supply and starve tumors, but it is restricted by poor efficacy and negative feedback-induced tumor relapse. In this study, a neuropilin-1 (NRP-1)-targeted nanomedicine (designated as FPPT@Axi) is reported for spatiotemporal tumor suppression by combining photodynamic therapy (PDT) with antiangiogenesis. In brief, FPPT@Axi is prepared by utilizing an NRP-1-targeting chimeric peptide (Fmoc-K(PpIX)-PEG8-TKPRR) to encapsulate the antiangiogenic drug Axitinib (Axi). Importantly, the NRP-1-mediated targeting property enables FPPT@Axi to selectively concentrate at vascular endothelial and breast cancer cells, facilitating the production of reactive oxygen species (ROS) in situ for specific vascular disruption and enhanced cell apoptosis under light stimulation. Moreover, the codelivered Axi can further inhibit vascular endothelial growth factor receptor (VEGFR) to impair the negative feedback of PDT-induced tumor neovascularization. Consequently, FPPT@Axi spatiotemporally restrains the tumor growth through blocking angiogenesis, destroying tumor vessels, and inducing tumor apoptosis. Such an NRP-1-mediated targeting codelivery system sheds light on constructing an appealing candidate with translational potential by using clinically approved PDT and chemotherapy.

Nuclear-targeted chimeric peptide nanorods to amplify innate anti-tumor immunity through localized DNA damage and STING activation.

Stimulator of the interferon genes (STING) pathway is appealing but challenging to potentiate the innate anti-tumor immunity. In this work, nuclear-targeted chimeric peptide nanorods (designated as PFPD) are constructed to amplify innate immunity through localized DNA damage and STING activation. Among which, the chimeric peptide (PpIX-FFVLKPKKKRKV) is fabricated with photosensitizer and nucleus targeting peptide sequence, which can self-assemble into nanorods and load STING agonist of DMXAA. The uniform nanosize distribution and good stability of PFPD improve the sequential targeting delivery of drugs towards tumor cells and nuclei. Under light irradiation, PFPD produce a large amount of reactive oxygen species (ROS) to destroy nuclear DNA in situ, and the released cytosolic DNA fragment will efficiently activate innate anti-tumor immunity in combination with STING agonist. In vitro and in vivo results indicate the superior ability of PFPD to activate natural killer cells and T cells, thus efficiently eradicating lung metastatic tumor without inducing unwanted side effects. This work provides a sophisticated strategy for localized activation of innate immunity for systemic tumor treatment, which may inspire the rational design of nanomedicine for tumor precision therapy.

MbEOMT1 regulates methyleugenol biosynthesis in Melaleuca bracteata F. Muell.

Methyleugenol, a bioactive compound in the phenylpropene family, undergoes its final and crucial biosynthetic transformation when eugenol O-methyltransferase (EOMT) converts eugenol into methyleugenol. While Melaleuca bracteata F. Muell essential oil is particularly rich in methyleugenol, it contains only trace amounts of its precursor, eugenol. This suggests that the EOMT enzyme in M. bracteata is highly efficient, although it has not yet been characterized. In this study, we isolated and identified an EOMT gene from M. bracteata, termed MbEOMT1, which is primarily expressed in the flowers and leaves and is inducible by methyl jasmonate (MeJA). Subcellular localization of MbEOMT1 in the cytoplasm was detected. Through transient overexpression experiments, we found that MbEOMT1 significantly elevates the concentration of methyleugenol in M. bracteata leaves. Conversely, silencing of MbEOMT1 via virus-induced gene silencing led to a marked reduction in methyleugenol levels. Our in vitro enzymatic assays further confirmed that MbEOMT1 specifically catalyzes the methylation of eugenol. Collectively, these findings establish that the MbEOMT1 gene is critical for methyleugenol biosynthesis in M. bracteata. This study enriches the understanding of phenylpropene biosynthesis and suggests that MbEOMT1 could serve as a valuable catalyst for generating bioactive compounds in the future.

Breaking Physical Barrier of Fibrotic Breast Cancer for Photodynamic Immunotherapy by Remodeling Tumor Extracellular Matrix and Reprogramming Cancer-Associated Fibroblasts.

Cancer-associated fibroblasts (CAFs) assist in breast cancer (BRCA) invasion and immune resistance by overproduction of extracellular matrix (ECM). Herein, we develop FPC@S, a photodynamic immunomodulator that targets the ECM, to improve the photodynamic immunotherapy for fibrotic BRCA. FPC@S combines a tumor ECM-targeting peptide, a photosensitizer (protoporphyrin IX) and an antifibrotic drug (SIS3). After anchoring to the ECM, FPC@S causes ECM remodeling and BRCA cell death by generating reactive oxygen species (ROS) in situ. Interestingly, the ROS-mediated ECM remodeling can normalize the tumor blood vessel to improve hypoxia and in turn facilitate more ROS production. Besides, upon the acidic tumor microenvironment, FPC@S will release SIS3 for reprograming CAFs to reduce their activity but not kill them, thus inhibiting fibrosis while preventing BRCA metastasis. The natural physical barrier formed by the dense ECM is consequently eliminated in fibrotic BRCA, allowing the drugs and immune cells to penetrate deep into tumors and have better efficacy. Furthermore, FPC@S can stimulate the immune system and effectively suppress primary, distant and metastatic tumors by combining with immune checkpoint blockade therapy. This study provides different insights for the development of fibrotic tumor targeted delivery systems and exploration of synergistic immunotherapeutic mechanisms against aggressive BRCA.

Self-reinforced photodynamic immunostimulator to downregulate and block PD-L1 for metastatic breast cancer treatment.

Tumor cells overexpress programmed cell death ligand 1 (PD-L1) to impede immune responses and escape immune elimination. Development of effective combination regimens to sensitize immunotherapy is promising but always challenging. Herein, a self-reinforced photodynamic immunostimulator (designated as PCS) is constructed for metastatic breast cancer treatment through simultaneous downregulation and blockade of PD-L1. Specifically, PCS is prepared by encapsulating signal transducer and activator of transcription 3 (STAT3) inhibitor (Stattic) into photosensitizer (protoporphyrin IX) modified PD-L1 blockade peptide (CVRARTR) through drug self-assembly. PCS can facilitate the targeted drug accumulation in PD-L1 overexpressed breast cancer cells to block PD-L1 and inhibit the phosphorylation of STAT3 to downregulate PD-L1. Moreover, PCS increases intracellular oxidative stress to show a robust anti-proliferation effect through photodynamic therapy (PDT), which also triggers an immunogenic cell death (ICD) to expose the immunostimulatory signals. Consequently, the efficient PD-L1 inhibition and robust PDT of PCS synergistically suppress the malignant growth of breast cancer, and concurrently activate the systemic anti-tumor immunity for metastatic inhibition with no obvious side effects. Such a photodynamic immunostimulator may provide an effective combination regimen for therapies activated immunotherapy against metastatic breast cancer.

The Role of MbEGS1 and MbEGS2 in Methyleugenol Biosynthesis by Melaleuca bracteata.

Many aromatic plant volatile compounds contain methyleugenol, which is an attractant for insect pollination and has antibacterial, antioxidant, and other properties. The essential oil of Melaleuca bracteata leaves contains 90.46% methyleugenol, which is an ideal material for studying the biosynthetic pathway of methyleugenol. Eugenol synthase (EGS) is one of the key enzymes involved in the synthesis of methyleugenol. We recently reported two eugenol synthase genes (MbEGS1 and MbEGS2) present in M. bracteata, where MbEGS1 and MbEGS2 were mainly expressed in flowers, followed by leaves, and had the lowest expression levels in stems. In this study, the functions of MbEGS1 and MbEGS2 in the biosynthesis of methyleugenol were investigated using transient gene expression technology and virus-induced gene silencing (VIGS) technology in M. bracteata. Here, in the MbEGSs genes overexpression group, the transcription levels of the MbEGS1 gene and MbEGS2 gene were increased 13.46 times and 12.47 times, respectively, while the methyleugenol levels increased 18.68% and 16.48%. We further verified the function of the MbEGSs genes by using VIGS, as the transcript levels of the MbEGS1 and MbEGS2 genes were downregulated by 79.48% and 90.35%, respectively, and the methyleugenol content in M. bracteata decreased by 28.04% and 19.45%, respectively. The results indicated that the MbEGS1 and MbEGS2 genes were involved in the biosynthesis of methyleugenol, and the transcript levels of the MbEGS1 and MbEGS2 genes correlated with the methyleugenol content in M. bracteata.

Effect of LLZO on the in situ polymerization of acrylate solid-state electrolytes on cathodes.

The comprehensive performance of the state-of-the-art solid-state electrolytes (SSEs) cannot match the requirements of commercial applications, and constructing an organic-inorganic composite electrolyte in situ on a porous electrode is an effective coping strategy. However, there are few studies focused on the influence of inorganic ceramics on the polymerization of multi-organic components. In this study, it was found that the addition of Li6.4La3Zr1.4Ta0.6O12 (LLZO) weakens the interaction between different polymers and makes organic and inorganic components contact directly in the solid electrolyte. These suppress the segregation of components in the in situ polymerized composite SSE, leading to a decrease in the polymer crystallization and improvement of electrolyte properties such as electrochemical stability window and mechanical properties. The composite solid-state electrolyte can be in situ constructed on different porous electrodes, which can establish close contact with active material particles, showing an ionic conductivity 4.4 × 10-5 S cm-1 at 25 °C, and afford the ternary cathode stability for 100 cycles.

Systematic Annotation Reveals CEP Function in Tomato Root Development and Abiotic Stress Response.

Tomato (Solanum lycopersicum) is one of the most important vegetable crops worldwide; however, environmental stressors severely restrict tomato growth and yield. Therefore, it is of great interest to discover novel regulators to improve tomato growth and environmental stress adaptions. Here, we applied a comprehensive bioinformatics approach to identify putative tomato C-TERMINALLY ENCODED PEPTIDE (CEP) genes and to explore their potential physiological function in tomato root development and abiotic stress responses. A total of 17 tomato CEP genes were identified and grouped into two subgroups based on the similarity of CEP motifs. The public RNA-Seq data revealed that tomato CEP genes displayed a diverse expression pattern in tomato tissues. Additionally, CEP genes expression was differentially regulated by nitrate or ammonium status in roots and shoots, respectively. The differences in expression levels of CEP genes induced by nitrogen indicate a potential involvement of CEPs in tomato nitrogen acquisition. The synthetic CEP peptides promoted tomato primary root growth, which requires nitric oxide (NO) and calcium signaling. Furthermore, we also revealed that CEP peptides improved tomato root resistance to salinity. Overall, our work will contribute to provide novel genetic breeding strategies for tomato cultivation under adverse environments.

CLE peptides join the plant longevity club.

Leaf senescence, the final step of leaf development, is an essential adaptive process that involves intricate regulatory networks mediated by various developmental and environmental clues. Two recent reports, by Zhang Z. et al. and Zhang Y. et al., shed light on how CLE peptides recruit reactive oxygen species (ROS) and ethylene signaling to promote plant leaf longevity.