Sialidase-Chimeric Bioengineered Bacteria for Tumor-Sialoglycan-Triggered Solid Tumor Therapy.

Adoptive cell therapies for solid tumors are usually limited by off-target antigens, incapable tissue infiltration, and cell function exhaustion. In contrast, bacterial cells possess the inherent competencies of preferential tumor targeting, deep tissue penetration, and high intratumoral bioactivity and represent promising alternatives to overcome these challenges. Here, a sialic-acid-responsive regulatory gene circuit is engineered into Escherichia coli MG1655 to express cytolysin of hemolysin E (HlyE). Furthermore, sialidases are bioorthogonally decorated onto the surface of azido-functionalized bioengineered bacteria for recognizing tumor sialoglycans and cleaving their sialosides into free sialic acids. As chemical inducers, sialic acids feedbackingly activate the bacterial gene circuit to produce HlyE and lyse tumor cells. This study mimics the tumor antigen-induced cytotoxin production and cell lysis that occurs in chimeric antigen receptor T (CAR-T) cells yet surmounts the intrinsic limitations of adoptive cell therapies. Moreover, sialidase-mediated tumor cell desialylation also reverses the immunosuppressive effect of glycoimmune checkpoints and further improves the therapeutic effect of solid tumors.

Immunoadjuvant-Modified Rhodobacter sphaeroides Potentiate Cancer Photothermal Immunotherapy.

Photothermal immunotherapy has become a promising strategy for tumor treatment. However, the intrinsic drawbacks like light instability, poor immunoadjuvant effect, and poor accumulation of conventional inorganic or organic photothermal agents limit their further applications. Based on the superior carrying capacity and active tumor targeting property of living bacteria, an immunoadjuvant-intensified and engineered tumor-targeting bacterium was constructed to achieve effective photothermal immunotherapy. Specifically, immunoadjuvant imiquimod (R837)-loaded thermosensitive liposomes (R837@TSL) were covalently decorated onto Rhodobacter sphaeroides (R.S) to obtain nanoimmunoadjuvant-armed bacteria (R.S-R837@TSL). The intrinsic photothermal property of R.S combined R837@TSL to achieve in situ near-infrared (NIR) laser-controlled release of R837. Meanwhile, tumor immunogenic cell death (ICD) caused by photothermal effect of R.S-R837@TSL, synergizes with released immunoadjuvants to promote maturation of dendritic cells (DCs), which enhance cytotoxic T lymphocytes (CTLs) infiltration for further tumor eradication. The photosynthetic bacteria armed with immunoadjuvant-loaded liposomes provide a strategy for immunoadjuvant-enhanced cancer photothermal immunotherapy.

Modularization of Regional Electronic Structure over Defect-Rich CeO2 Rods for Enhancing Photogenerated Charge Transfer and CO2 Activation.

Oxygen vacancy (OV) engineering has been widely applied in different types of metal oxide-based photocatalytic reactions. Our study has shown that the redistributed OVs resulting from voids in CeO2 rods lead to significant differences in the band structure in space. The flat energy band within the highly crystallized bulk region hinders the recombination of photogenerated carrier pairs during the transfer process. The downward curved energy band in the surface region enhances the activation of the absorbents. Therefore, the localization of the band structure through crystal structure regionalization renders V-CeO2 capable of achieving efficient utilization of photogenerated carriers. Practically, the V-CeO2 rod shows a remarkable turnover number of 190.58 µmol g-1 h-1 in CO2 photoreduction, which is ∼9.4 times higher than that of D-CeO2 (20.46 µmol g-1 h-1). The designed modularization structure in our work is expected to provide important inspiration and guidance in coordinating the kinetic behavior of carriers in OV defect-rich photocatalysts.

DNA Nanostructures: Advancing Cancer Immunotherapy.

Cancer immunotherapy is a groundbreaking medical revolution and a paradigm shift from traditional cancer treatments, harnessing the power of the immune system to target and destroy cancer cells. In recent years, DNA nanostructures have emerged as prominent players in cancer immunotherapy, exhibiting immense potential due to their controllable structure, surface addressability, and biocompatibility. This review provides an overview of the various applications of DNA nanostructures, including scaffolded DNA, DNA hydrogels, tetrahedral DNA nanostructures, DNA origami, spherical nucleic acids, and other DNA-based nanostructures in cancer immunotherapy. These applications explore their roles in vaccine development, immune checkpoint blockade therapies, adoptive cellular therapies, and immune-combination therapies. Through rational design and optimization, DNA nanostructures significantly bolster the immunogenicity of the tumor microenvironment by facilitating antigen presentation, T-cell activation, tumor infiltration, and precise immune-mediated tumor killing. The integration of DNA nanostructures with cancer therapies ushers in a new era of cancer immunotherapy, offering renewed hope and strength in the battle against this formidable foe of human health.

The RAS-signaling-pathway-mutation-related prognosis in B-cell acute lymphoblastic leukemia: A report from South China children's leukemia group.

The next-generation sequencing technologies application discovers novel genetic alterations frequently in pediatric acute lymphoblastic leukemia (ALL). RAS signaling pathway mutations at the time of relapse ALL frequently appear as small subclones at the time of onset, which are considered as the drivers in ALL relapse. Whether subclones alterations in the RAS signaling pathway should be considered for risk group stratification of ALL treatment is not decided yet. In this work, we investigate the RAS signaling pathway mutation spectrum and the related prognosis in pediatric ALL. We employed an NGS panel comprising 220 genes. NGS results were collected from 202 pediatric ALL patients. 155 patients (76.7%) harbored at least one mutation. The incidences of RAS signaling pathway mutations are different significantly between T-ALL and B-ALL. In B-ALL, the RAS pathway is mostly involved, and NRAS (17.6%), KRAS (22.7%), and PTPN11 (7.7%) were the three most frequently mutated genes. Co-occurring mutations of CREBBP and NRAS, FLT3, or PTPN11 (p = 0.002, p = 0.009, and p = 0.003, respectively) were found in this cohort. The 3-year RFS rates for the RAS signaling pathway mutation-positive and negative cases was 76.5 % versus 89.7 % (p = 0.012). Four cases relapsed in the lately 3 years were RAS signaling pathway mutation-positive. RAS signaling pathway mutation is an important biomarker for poorer relapse-free survival in pediatric B-ALL patients despite good early MRD levels.

Intracellular Gelation-Mediated Living Bacteria for Advanced Biotherapeutics in Mouse Models.

Despite its significant potential in various disease treatments and diagnostics, microbiotherapy is consistently plagued by multiple limitations ranging from manufacturing challenges to in vivo functionality. Inspired by the strategy involving nonproliferating yet metabolically active microorganisms, we report an intracellular gelation approach that can generate a synthetic polymer network within bacterial cells to solve these challenges. Specifically, poly(ethylene glycol dimethacrylate) (PEGDA, 700 Da) monomers are introduced into the bacterial cytosol through a single cycle of freeze-thawing followed by the initiation of intracellular free radical polymerization by UV light to create a macromolecular PEGDA gel within the bacterial cytosol. The molecular crowding resulting from intracytoplasmic gelation prohibits bacterial division and confers robust resistance to simulated gastrointestinal fluids and bile acids while retaining the ability to secrete functional proteins. Biocompatibility assessments demonstrate that the nondividing gelatinized bacteria are effective in alleviating systemic inflammation triggered by intravenous Escherichia coli injection. Furthermore, the therapeutic efficacy of gelatinized Lactobacillus rhamnosus in colitis mice provides additional support for this approach. Collectively, intracellular gelation indicates a universal strategy to manufacture next-generation live biotherapeutics for advanced microbiotherapy.

Accurate Structural Elucidation of Samoquasine A and an Unknown Homologue Using a Computation-Based Machine Learning Protocol.

The structure of samoquasine A has long been a subject of controversy, which was resolved only upon its successful total synthesis. We examined the structures of the associated compounds using the state-of-the-art SVM-M protocol. The method accurately discriminated all putative structures historically attributed to samoquasine A from a pool of 48 isomeric structures, confirming that samoquasine A is indeed identical to perlolidine. Furthermore, by applying the SVM-M protocol to an additional pool of 67 isomeric structures, we successfully assigned a yet unknown natural product, initially misidentified as perlolidine, as a novel oxime, (E)-3H-cyclopenta[c]quinolin-3-one oxime, representing the first reported cyclone oxime-quinoline natural product.

Office-based vergence and anti-suppression therapy for the treatment of small-to-moderate angle intermittent exotropia: A randomised clinical trial.

PURPOSE: To evaluate the short-term (1 week after completion of treatment) effect of office-based vergence and anti-suppression therapy (OBVAT) on the Office Control Score when compared to observation alone in children with small-to-moderate angle intermittent exotropia (IXT). METHODS: In this single-masked (examiner masked), two-arm, single-centre randomised clinical trial, 40 participants, 6 to <18 years of age with untreated IXT, were randomly assigned to OBVAT or observation alone. Participants assigned to therapy received 60 min of OBVAT with home reinforcement once per week for 16 weeks. Therapy included vergence, accommodation and anti-suppression techniques. The primary outcome measure was the comparison of the distance Office Control Score between the two groups at the primary outcome visit (i.e., 17-week follow-up visit). RESULTS: At the primary outcome visit, the OBVAT group (n = 20) had a significantly better distance Office Control Score (adjusted mean difference: -0.9; 95% CI: -0.2 to -1.5; p = 0.008; partial eta squared: 0.19) than the observation group (n = 16). Participants from the OBVAT group were more likely than those from the observation group to have ≥1 point of improvement at the 17-week visit (OBVAT group: 75%; Observation group: 25%; p = 0.006). CONCLUSIONS: In this randomised clinical trial of participants aged 6 to <18 years with IXT, we found that the OBVAT group had a significantly better distance Office Control Score than the observation group at the 17-week visit. This study provides the first data from a randomised clinical trial demonstrating the effectiveness of OBVAT for improving the control of IXT. Eye care practitioners should consider OBVAT as a viable, non-surgical treatment option for IXT. A full-scale randomised clinical trial investigating the long-term effectiveness of OBVAT in treating IXT is warranted.

Two-Pronged Microbe Delivery of Nitric Oxide and Oxygen for Diabetic Wound Healing.

Chronic inflammation and hypoxia in the microenvironment of diabetic foot ulcers (DFUs) can result in sustained vascular impairment, hindering tissue regeneration. While both nitric oxide and oxygen have been shown to promote wound healing in DFUs through anti-inflammatory and neovascularization, there is currently no available therapy that delivers both. We present a novel hydrogel consisting of Weissella and Chlorella, which alternates between nitric oxide and oxygen production to reduce chronic inflammation and hypoxia. Further experiments indicate that the hydrogel accelerates wound closure, re-epithelialization, and angiogenesis in diabetic mice and improves the survival of skin grafts. This dual-gas therapy holds promise as a potential treatment option for the management of diabetic wounds.

Autonomously Assembled Living Capsules by Microbial Coculture for Enhanced Bacteriotherapy of Inflammatory Bowel Disease.

Microorganism-mediated self-assembling of living formulations holds great promise for disease therapy. Here, we constructed a prebiotic-probiotic living capsule (PPLC) by coculturing probiotics (EcN) with Gluconacetobacter xylinus (G. xylinus) in a prebiotic-containing fermentation broth. Through shaking the culture, G. xylinus secretes cellulose fibrils that can spontaneously encapsulate EcN to form microcapsules under shear forces. Additionally, the prebiotic present in the fermentation broth is incorporated into the bacterial cellulose network through van der Waals forces and hydrogen bonding. Afterward, the microcapsules were transferred to a selective LB medium, which facilitated the colonization of dense probiotic colonies within them. The in vivo study demonstrated that PPLC-containing dense colonies of EcN can antagonize intestinal pathogens and restore microbiota homeostasis by showing excellent therapeutic performance in treating enteritis mice. The in situ self-assembly of probiotics and prebiotics-based living materials provides a promising platform for the treatment of inflammatory bowel disease.