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Cytotherapy is a strategy to deliver modified cells to a diseased tissue, but targeting solid tumours remains challenging. Here we design macrophages, harbouring a surface glypican-3-targeting peptide and carrying a cargo to combat solid tumours. The anchored targeting peptide facilitates tumour cell recognition by the engineered macrophages, thus enhancing specific targeting and phagocytosis of tumour cells expressing glypican-3. These macrophages carry a cargo of the TLR7/TLR8 agonist R848 and INCB024360, a selective indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, wrapped in C16-ceramide-fused outer membrane vesicles (OMV) of Escherichia coli origin (RILO). The OMVs facilitate internalization through caveolin-mediated endocytosis, and to maintain a suitable nanostructure, C16-ceramide induces membrane invagination and exosome generation, leading to the release of cargo-packed RILOs through exosomes. RILO-loaded macrophages exert therapeutic efficacy in mice bearing H22 hepatocellular carcinomas, which express high levels of glypican-3. Overall, we lay down the proof of principle for a cytotherapeutic strategy to target solid tumours and could complement conventional treatment. Macrophages are considered a good candidate for cancer cytotherapy because of their phagocytotic capacity, enabling them to deliver cargo to tissues. Here authors engineer macrophages that are targeted to glypican-3-expressing tumour cells and equipped with drug-loaded exosomes and show therapeutic efficiency in a mouse model of hepatocellular cancer.

Background The complement system plays an important role in many neurological disorders. Complement modulation, including C3/C3a receptor signaling, shows promising therapeutic effects on cognition and neurodegeneration. Yet, the implications for this pathway in perioperative neurocognitive disorders (PND) are not well established. Here, we evaluated the possible role for C3/C3a receptor signaling after orthopedic surgery using an established mouse model of PND. Methods A stabilized tibial fracture surgery was performed in adult male C57BL/6 mice under general anesthesia and analgesia to induce PND-like behavior. Complement activation was assessed in the hippocampus and choroid plexus. Changes in hippocampal neuroinflammation, synapse numbers, choroidal blood-cerebrospinal fluid barrier (BCSFB) integrity, and hippocampal-dependent memory function were evaluated after surgery and treatment with a C3a receptor blocker. Results C3 levels and C3a receptor expression were specifically increased in hippocampal astrocytes and microglia after surgery. Surgery-induced neuroinflammation and synapse loss in the hippocampus were attenuated by C3a receptor blockade. Choroidal BCSFB dysfunction occurred 1 day after surgery and was attenuated by C3a receptor blockade. Administration of exogenous C3a exacerbated cognitive decline after surgery, whereas C3a receptor blockade improved hippocampal-dependent memory function. Conclusions Orthopedic surgery activates complement signaling. C3a receptor blockade may be therapeutically beneficial to attenuate neuroinflammation and PND.

Although the relationship between the incorporation of an element into otoliths and the concentration of the element in water has been extensively investigated in many fish species, the interactive effects of multiple elements in water on the otolith incorporation of an element are not adequately explored or well understood. In this study, 16 treatments in triplicate using strontium (Sr; 1, 2, 3 and 4 times the ambient baseline, 6.5 mg l-1) and barium (Ba; 1, 2, 4 and 6 times the ambient baseline, 40 μg l-1) as categorical variables in an orthogonal design were established to evaluate the relative or interactive effects of water elements on otolith elemental incorporation in juvenile flounder Paralichthys olivaceus (from 15 to 116 days post hatching). The results revealed that otolith incorporation (Me:CaOtolith) of Sr and Ba were positively dependent on the concentrations of the elements in water (Me:CaWater). Overall, Sr was incorporated into otoliths more efficiently than was Ba, and the partition efficiency (DMe) of both elements decreased with increasing water elemental concentrations. Increasing Sr concentrations in water appeared to negatively affect the uptake of Ba into otoliths rather than facilitate it, as previously reported in fish reared in freshwater and brackish water, or showed no effect on fish in seawater. Conversely, the Ba concentration in water did not influence the otolith uptake of Sr, which agrees with the findings for other fish species. When applying otolith microchemistry to fish ecology studies, it is essential to cautiously address the interactive effects of multiple elements in the environment on otolith elemental incorporation.

An estrogen (ES)-functionalized cationic liposomal system was developed and exploited for targeted delivery to osteosarcoma. Natural biocompatible chotooligosaccharides (COS, MW2-5 KDa) were covalently tethered to the liposomal surface through a disulfate bond (-SS-) to confer reduction-responsive COS detachment, whereas estrogen was grafted via polyethylene glycol (PEG 2 K) chain to achieve estrogen receptor-targeting. The liposomal carriers were prepared by the ethanol injection method and fluorescent anticancer drug doxorubicin (DOX) was loaded with ammonium sulfate gradient. The physicochemical properties, reduction-sensitivity, and the roles of estrogen on cellular uptake and tumor-targeting were studied. The Chol-SS-COS/ES/DOX liposomes were spherical with an average size about 110 nm, and high encapsulation efficiency. The liposomes were stable in physiological condition but rapidly release the payload in response to tumoral intracellular glutathione (20 mM). MTT cytotoxicity assay confirmed that Chol-SS-COS/ES/DOX liposomes exhibited higher cytotoxicity to MG63 osteosarcoma cells than to liver cells (LO2). Flow cytometry (FCM) and confocal laser scanning microscopy revealed that cellular uptake of Chol-SS-COS/ES/DOX liposomes by MG63, than the free DOX or Chol-SS-COS/DOX. Ex vivo fluorescence distribution study showed that the multifunctional liposomes selectively accumulated in the MG63 xenografts versus the organs. Chol-SS-COS/ES/DOX liposomes strongly inhibited the tumor growth and enhanced the animal survival rate. Overall, the COS grafted estrogen-functionalized cationic liposomes, fortified with glutathione-responsiveness, showed great potential for specific intracellular drug delivery to estrogen receptor-expressing tumors such as osteosarcoma.

Effective presentation of antigens by dendritic cells (DC) is essential for achieving a robust cytotoxic T lymphocytes (CTLs) response, in which cDC1 is the key DC subtype for high‐performance activation of CTLs. However, low cDC1 proportion, complex process, and high cost severely hindered cDC1 generation and application. Herein, the study proposes an in situ cDC1 recruitment and activation strategy with simultaneous inhibiting cancer stemness for inducing robust CTL responses and enhancing the anti‐tumor effect. Fms‐like tyrosine kinase 3 ligand (FLT3L), Poly I:C, and Nap‐CUM (NCUM), playing the role of cDC1 recruitment, cDC1 activation, inducing antigen release and decreasing tumor cell stemness, respectively, are co‐encapsulated in an in situ hydrogel vaccine (FP/NCUM‐Gel). FP/NCUM‐Gel is gelated in situ after intra‐tumoral injection. With the near‐infrared irradiation, tumor cell immunogenic cell death occurred, tumor antigens and immunogenic signals are released in situ. cDC1 is recruited to tumor tissue and activated for antigen cross‐presentation, followed by migrating to lymph nodes and activating CTLs. Furthermore, tumor cell stemness are inhibited by napabucasin, which can help CTLs to achieve comprehensive tumor killing. Collectively, the proposed strategy of cDC1 in situ recruitment and activation combined with stemness inhibition provides great immune response and anti‐tumor potential, providing new ideas for clinical tumor vaccine design. An in situ hydrogel vaccine is fabricated by co‐encapsulating Fms‐like tyrosine kinase 3 ligand (FLT3L), Poly I:C, and Nap‐Ce6/UCM (NCUM). Ce6 triggered Photodynamic therapy (PDT) induces tumor antigens release in situ. cDC1 is recruited to tumor tissue and activated for cross‐presentation, followed by migrating to lymph nodes and activating CTLs. Tumor stemness is inhibited by napabucasin, which helps CTLs to achieve comprehensive tumor killing.

Liver cancer, especially hepatocellular carcinoma, is an important cause of cancer-related death, and its incidence is increasing worldwide. Nano drug delivery systems have shown great promise in the treatment of cancers. In order to improve their therapeutic efficacy, it is very important to realize the high accumulation and effective release of drugs at the tumor site. In this manuscript, using doxorubicin (DOX) as a model drug, CD13-targeted mesoporous silica nanoparticles coated with NGR-peptide-modified pegylated carboxymethyl chitosan were constructed (DOX/MSN-CPN). DOX/MSN-CPN comprises a spherical shape with an obvious capping structure and a particle size of 125.01 ± 1.52 nm. With a decrease in pH, DOX/MSN-CPN showed responsive desorption from DOX/MSN-CPN and pH-responsive release of DOX was observed. Meanwhile, DOX/MSN-CPN could be efficiently absorbed through NGR-mediated internalization in vitro and could efficiently deliver DOX to tumor tissues with long accumulation times in vivo, suggesting good active targeting properties. Moreover, significant tumor inhibition has been observed in antitumor studies in vivo. This study provides a strategy of utilizing DOX/MSN-CPN as a nano-platform for drug delivery, which has superb therapeutic efficacy and safety for the treatment of hepatocellular carcinoma both in vivo and in vitro.

Tumor immune escape caused by low levels of tumor immunogenicity and immune checkpoint‐dependent suppression limits the immunotherapeutic effect. Herein, a “two‐way regulation” epigenetic therapeutic strategy is proposed using a novel nano‐regulator that inhibits tumor immune escape by upregulating expression of tumor‐associated antigens (TAAs) to improve immunogenicity and downregulating programmed cell death 1 ligand 1 (PD‐L1) expression to block programmed death‐1 (PD‐1)/PD‐L1. To engineer the nano‐regulator, the DNA methyltransferase (DNMT) inhibitor zebularine (Zeb) and the bromodomain‐containing protein 4 (BRD4) inhibitor JQ1 are co‐loaded into the cationic liposomes with condensing the toll‐like receptor 9 (TLR9) agonist cytosine‐phosphate‐guanine (CpG) via electrostatic interactions to obtain G‐J/ZL. Then, asparagine–glycine–arginine (NGR) modified material carboxymethyl‐chitosan (CMCS) is coated on the surface of G‐J/ZL to construct CG‐J/ZL. CG‐J/ZL is shown to target tumor tissue and disassemble under the acidic tumor microenvironment (TME). Zeb upregulated TAAs expression to improve the immunogenicity; JQ1 inhibited PD‐L1 expression to block immune checkpoint; CpG promote dendritic cell (DC) maturation and reactivated the ability of tumour‐associated macrophages (TAM) to kill tumor cells. Taken together, these results demonstrate that the nano‐regulator CG‐J/ZL can upregulate TAAs expression to enhance T‐cell infiltration and downregulate PD‐L1 expression to improve the recognition of tumor cells by T‐cells, representing a promising strategy to improve antitumor immune response. The “two‐way regulation” epigenetic therapy strategy via designing an integrated nano‐regulator is proposed to inhibit tumor immune escape, which can upregulate tumor‐associated antigens (TAAs) expression to enhance T‐cell infiltration and downregulate PD‐L1 expression to improve the recognization of T‐cells to tumor cells, thus inhibiting tumor immune escape and activating antitumor immune response.

This study adopted two risk assessment models to estimate the potential risk of heavy metals (HMs) in agricultural soils from a high Cd geological background area. Results were as follows: HMs posed an extremely high potential ecological risk (PER) (PER = 2051 > 1200) ascribed to Cd contribution. The overall non-carcinogenic risk (HI) of HMs for children (HI > 1) was unacceptable. Contributions of HMs to HI generally decreased in the order of Cr > As > Pb > Cd > Ni > Cu > Zn. The total carcinogenic risk (TCR) value for adults (2.1 × 10–4) and children (2.2 × 10–4) surpassed the reference value (1.0 × 10–4), indicating that the risks were unacceptable. Contributions of HMs to TCR generally decreased in the order of Cr ≈ Ni > Cd > As > Pb. These results suggested that risk control policies should not only consider the potential ecological risk of Cd but also take into consideration of the carcinogenic and non-carcinogenic risk of Cr and Ni in a typically high Cd geological background area.

Thickness nonuniformity is a bottleneck in the micro electroforming process of micro-metal devices. In this paper, a new method of fabricating a layered auxiliary cathode is proposed to improve the thickness uniformity of a micro-electroforming layer. In order to analyze the general applicability of the proposed method, four basic microstructures, namely circular, square, regular triangular, and regular hexagonal were used to study the effect of a layered auxiliary cathode on thickness uniformity through simulation and experimentation. The simulation results showed that with the help of the proposed auxiliary cathode, the thickness nonuniformity of four microstructures should decrease due to the reduced edge effect of the current density. The experimental results showed that the thickness uniformity of four microstructures fabricated via the proposed method was improved by 190.63%, 116.74%, 80.43%, and 164.30% compared to that fabricated via the traditional method, respectively. Meanwhile, the micro-gear was fabricated and the nonuniformity was reduced by 101.15% using the proposed method.

Probiotics are considered an effective strategy for relieving DSS-induced colitis. This study investigated the protective effects and mechanisms of Aspergillus cristatum, a potential probiotic fungus from Fuzhuan brick tea, on colitis. Supplementation with live 102 spores/mL of A. cristatum H-1 and 105 spores/mL of A. cristatum S-6 significantly improved gut integrity by preventing colon shortening, mucus disruption, and goblet cell depletion. Additionally, it significantly reduced proinflammatory cytokines IL-6 and TNF-α levels, enhanced the expression of tight junction molecules (ZO-1, Claudin-1, E-cadherin, and MUC1) and suppressed the NLRP3 signaling pathway. Live A. cristatum H-1 (102 spores/mL) and A. cristatum S-6 (105 spores/mL) can effectively improve colitis. But the inactivated A. cristatum H-1 did not exhibit effective anti-inflammatory effects and significant interspecies differences. In a word, live low-dose A. cristatum H-1 and high-dose A. cristatum S-6 promise a valuable approach to improving colitis. This research not only enhances our understanding of probiotics and their potential therapeutic uses but also sets the stage for future investigations into the mechanisms of action and clinical utilization of A. cristatum in treating colitis and other gut disorders.