Sonodynamic therapy, a treatment modality recently widely used, is capable of disrupting the tumor microenvironment by inducing immunogenic cell death (ICD) and enhancing antitumor immunity during immunotherapy. Erdafitinib, an inhibitor of the fibroblast growth factor receptor, has demonstrated potential benefits for treating bladder cancer. However, Erdafitinib shows effectiveness in only a small number of patients, and the majority of patients responding positively to the medication have "immune-cold" tumors. To increase the therapeutic efficacy of Erdafitinib, we have herein developed a biodegradable pseudoconjugate polymer (PSP) with sonodynamic capabilities. Erdafitinib could be efficiently encapsulated in nanoparticles (NP-PE) prepared through the self-assembly of PSP with an oxidation-sensitive polymer (P1). Under ultrasound conditions, NP-PE effectively induced cytotoxicity by producing reactive oxygen species and further triggering ICD. Compared with Erdafitinib, NP-PE inhibited the expression of FGFR3 to a higher extent. In animal models with bladder cancer, NP-PE inhibited tumor growth, stimulated antitumor immunity, and synergized with antiprogrammed cell death-ligand 1 (aPD-L1), offering a novel approach for the treatment of bladder cancer.
Abstract Complex coacervation enables important wet adhesion processes in natural and artificial systems. However, existed synthetic coacervate adhesives show limited wet adhesion properties, non‐thermoresponsiveness, and inferior biodegradability, greatly hampering their translations. Herein, by harnessing supramolecular assembly and rational protein design, we present a temperature‐sensitive wet bioadhesive fabricated through recombinant protein and surfactant. Mechanical performance of the bioglue system is actively tunable with thermal triggers. In cold condition, adhesion strength of the bioadhesive was only about 50 kPa. By increasing temperature, the strength presented up to 600 kPa, which is remarkably stronger than other biological counterparts. This is probably due to the thermally triggered phase transition of the engineered protein and the formation of coacervate, thus leading to the enhanced wet adhesion bonding.
Abstract Atomically precise ~1‐nm Pt nanoparticles (nanoclusters, NCs) with ambient stability are important in fundamental research and exhibit diverse practical applications (catalysis, biomedicine, etc.). However, synthesizing such materials is challenging. Herein, by employing the mixture ligand protecting strategy, we successfully synthesized the largest organic‐ligand‐protected (~1‐nm) Pt 23 NCs precisely characterized with mass spectrometry and single‐crystal X‐ray diffraction analyses. Interestingly, natural population analysis and Bader charge calculation indicate an alternate, varying charge ‐layer distribution in the sandwich‐like Pt 23 NC kernel. Pt 23 NCs can catalyze the oxygen reduction reaction under acidic conditions without requiring calcination and other treatments, and the resulting specific and mass activities without further treatment are sevenfold and eightfold higher than those observed for commercial Pt/C catalysts, respectively. Density functional theory and d ‐band center calculations interpret the high activity. Furthermore, Pt 23 NCs exhibit a photothermal conversion efficiency of 68.4 % under 532‐nm laser irradiation and can be used at least for six cycles, thus demonstrating great potential for practical applications.
Group 2 innate lymphoid cells (ILC2s) are recently reported to play a more critical role in allergic diseases. We previously identified that mesenchymal stromal cells (MSCs) elicited therapeutic effects on allergic airway inflammation. Small extracellular vesicles (sEV) derived from MSCs possess striking advantages including low immunogenicity and high biosafety, and is extremely promising cell-free therapeutic agents. However, the effects of MSC-sEV on ILC2s are still unclear. Additionally, scalable isolation protocols are required for the mass production of homogenous MSC-sEV especially in clinical application. We previously reported that induced pluripotent stem cells-derived MSCs were the ideal cellular source for the large preparation of MSC-sEV. Here we developed a standardized scalable protocol of anion-exchange chromatography for isolation of MSC-sEV, and investigated the effects of MSC-sEV on ILC2 function from patients with allergic rhinitis and in a mouse ILC2-dominant asthma model. The characterization of MSC-sEV was successfully demonstrated in terms of size, morphology and specific markers. Using flow cytometry and human Cytokine Antibody Array, MSC-sEV but not fibroblasts-sEV (Fb-sEV) were found to significantly inhibit the function of human ILC2s. Similarly, systemic administration of MSC-sEV but not Fb-sEV exhibited an inhibition of ILC2 levels, inflammatory cell infiltration and mucus production in the lung, a reduction in levels of T helper 2 cytokines, and alleviation of airway hyperresponsiveness in a mouse model of asthma. Using RNA sequencing, miR-146a-5p was selected as the candidate to mediate the above effects of MSC-sEV. We next revealed the uptake of ILC2s to MSC-sEV, and that transfer of miR-146a-5p in MSC-sEV to ILC2s in part contributed to the effects of MSC-sEV on ILC2s in vitro and in a mouse model. In conclusion, we demonstrated that MSC-sEV were able to prevent ILC2-dominant allergic airway inflammation at least partially through miR-146a-5p, suggesting that MSC-sEV could be a novel cell-free strategy for the treatment of allergic diseases.
Abstract The development of new storage media to meet the demands for diverse information storage scenarios is a great challenge. Here, a series of lanthanide‐based luminescent organogels with ultrastrong mechanical performance and outstanding plasticity are developed for patterned information storage and encryption applications. The organogels possessing outstanding mechanical properties and tunable luminescent colors are prepared by electrostatic and coordinative interactions between natural DNA, synthetic ligands, and rare earth (RE) ions. The organogel‐REs can be stretched by 180 times and show an ultrastrong breaking strength of 80 MPa. A series of applications with both information storage and encryption, such as self‐information pattern, quick response (QR) code, and barcode, are successfully demonstrated by the organogel‐REs. The developed information storage systems have various advantages of good processability, high stretchability, excellent stability, and versatile design of information patterns. Therefore, the organogel‐RE‐based information storage systems are suitable for applications under different scenarios, such as flexible devices under repeating rude operations. The advancements will enable the design and development of luminescent organogel‐REs as information storage and encryption media for various scenarios.
Abstract Four reactive liquid rubbers with different end‐groups but the same main chain (carboxyl‐, epoxy‐, amino‐terminated and non‐functional butadiene–acrylonitrile random copolymers) were employed in the same epoxy system, the diglycidyl ether of bisphenol A and 4,4′‐diamino‐3,3′‐dimethyldicyclohexyl methane cured at 50°C. The effects of the end‐groups of the liquid rubber on the morphology, phase compositions, sub‐structure inside the particles, interface between the phases and the mechanical properties were determined. The effects were related to the reactivity and the miscibility of the additive.
Transmembrane 6 superfamily 1 (TM6SF1) is lowly expressed in lung adenocarcinoma (LUAD), but the function and mechanisms of TM6SF1 remain unclear. Thus, we attempt to explore the function of TM6SF1 and its underlying mechanisms in LUAD. qRT-PCR was used for detecting TM6SF1 mRNA expression. Immunohistochemistry staining was used for detecting the expression of MMP-2, TM6SF1, Ki67, MMP-9, and CD163 proteins. E-cadherin, p-PI3K, Vimentin, AKT, N-cadherin, PI3K, p-AKT, mTOR, p-mTOR, and marker proteins of M2 macrophages were evaluated using Western blot. CD206 protein expression was examined via immunofluorescence. The IL-10 concentration was measured via enzyme-linked immunosorbent assay (ELISA). Using CCK-8, colony formation and transwell assays, cell proliferation, migration, and invasion were assessed. A549 cells were injected into the mice's flank for establishing a mouse tumor model and into the tail vein for establishing the lung metastasis model. HE staining was performed to detect pathological changes in lung tissues. Decreased TM6SF1 expression was found in LUAD tissues and cells. TM6SF1 overexpression inhibited cell viability, proliferation, invasion, migration, EMT, and polarization of M2 macrophages in LUAD cells, along with tumor growth and metastasis in xenograft mice. Bioinformatics analysis demonstrated that TM6SF1 was correlated with the tumor microenvironment. TM6SF1 overexpression reduced expression levels of p-mTOR, p-PI3K, p-AKT, mTOR, and AKT. TM6SF1-caused inhibition of proliferation, migration, invasion and EMT, as M2 macrophage polarization was reversed by the PI3K activator in LUAD cells. TM6SF1 inactivated the PI3K/AKT/mTOR pathway to suppress LUAD malignancy and polarization of M2 macrophages, providing insight for developing new LUAD treatments.
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