Human natural killer cells for targeting delivery of gold nanostars and bimodal imaging directed photothermal/photodynamic therapy and immunotherapy

Objective:To construct a novel nanoplatform GNS@CaCO3/Ce6-NK by loading the CaCO3-coated gold nanostars(GNSs)with Chlorin e6 molecules(Ce6)into human peripheral blood mononuclear cells(PBMCs)-derived NK cells for tumor targeted therapy.Methods:GNS@CaCO3/Ce6 nanoparticles were prepared and characterized by TEM and UV-vis.The cell surface markers and cytokines secretion of NK cells before and after loading the GNS@CaCO3/Ce6 nanoparticles were detected by Flow Cytometry(FCM)and ELISA.Effects of the GNS@CaCO3/Ce6-NK cells on A549 cancer cells was determined by FCM and CCK-8.Intracellular fluorescent signals of GNS@CaCO3/Ce6-NK cells were detected via Confocal laser scanning microscopic(CLSM)and FCM at different time points.Intracellular ROS generation of GNS@CaCO3/Ce6-NK cells under laser irradiation were examined by FCM.The distribution of GNS@CaCO3/Ce6-NK in A549 tumor-bearing mice were observed by fluorescence imaging and PA imaging.The combination therapy of GNS@CaCO3/Ce6-NK under laser irradiation were investigated on tumor-bearing mice.Results:The coated CaC03 shell on the surface of GNSs exhibited prominent delivery and protection effect of Ce6 during the cellular uptake process.The as-prepared multifunctional GNS@CaCO3/Ce6-NK cells possessed bimodal functions of fluorescence imaging and photoacoustic imaging.The as-prepared multifunctional GNS@CaCO3/Ce6-NK cells could actively target tumor tissues with the enhanced photothermal/photodynamic therapy and immunotherapy.Conclusions:The GNS@CaCO3/Ce6-NK shows effective tumor-targeting ability and prominent therapeutic efficacy toward lung cancer A549 tumor-bearing mice.Through fully utilizing the features of GNSs and NK cells,this new nanoplatform provides a new synergistic strategy for enhanced photothermal/photodynamic therapy and immunotherapy in the field of anticancer development in the near future.

Human iPS Cells Loaded with MnO2-Based Nanoprobes for Photodynamic and Simultaneous Enhanced Immunotherapy Against Cancer

How to trigger strong anti-tumor immune responses has become a focus for tumor therapy.Here,we report the human-induced pluripotent stem cells(iPSs)to deliver MnO2@Ce6 nanoprobes into tumors for simultaneous photodynamic therapy(PDT)and enhanced immunotherapy.Ce6 photosensitizer was attached on manganese dioxide(MnO2)nanoparticles,and resultant MnO2@Ce6 nanoprobes were delivered into mitomycin-treated iPSs to form iPS-MnO2@Ce6 nanoprobes.The iPS-MnO2@Ce6 actively targeted in vivo tumors,the acidic microenvironment triggered interaction between MnO2 and H2O2,released large quantities of oxygen,alleviated hypoxia in tumor.Upon PDT,singlet oxygen formed,broken iPSs released tumor-shared antigens,which evoked an intensive innate and adaptive immune response against the tumor,improving dendritic cells matured,effector T cells,and natural killer cells were activated.Meanwhile,regulatory T cells were reduced,and then the immune response induced by iPS-MnO2@Ce6 was markedly stronger than the immune reaction induced by MnO2@Ce6(P<0.05).The iPS-MnO2@Ce6 markedly inhibited tumor growth and metastasis and reduced mortality in mice models with tumor.Human iPS s loaded with MnO2-based nanoprobes are a promising strategy for simultaneous PDT and enhanced immunotherapy against tumor and own clinical translational prospect.

Dual-targeted lung cancer therapy via inhalation delivery of UCNP-siRNA-AS1411 nanocages

Objective:Although great progress has been made in the field of siRNA gene therapy,safe,efficient,and targeted delivery of siRNA are still major challenges in siRNA therapeutics.Methods:We developed an up-conversion nanoparticle-based nanocage system.This system protected the siRNA from being degraded by nucleases in organisms and selectively delivered the siRNAs to the tumor sites,due to modifications of targeted molecules on the surfaces of nanocages and local inhalation.Results:The siRNAs delivered by the up-conversion nanoparticle nanocages were protected from degradation in transit to the tumor sites,where they accumulated.Compared with the passive target and control groups,the up-conversion nanoparticles based on the nanocage system showed a tumor suppressive effect after approximately 3 weeks of treatment.Conclusions:The up-conversion nanoparticle nanocages efficiently delivered vascular endothelial growth factor siRNAs to tumor sites.Mice with lung tumors treated with tumors targeting up-conversion nanoparticle nanocages showed steady body weight changes,high tumor inhibition ratios,and longer survival times.

Artificial intelligence in theranostics of gastric cancer, a review

Gastric cancer (GC) is one of the commonestcancers with high morbidity and mortality in the world.How to realize precise diagnosis and therapy of GC ownsgreat clinical requirement. In recent years, artificial intelligence (AI) has been actively explored to apply to earlydiagnosis and treatment and prognosis of gastric carcinoma. Herein, we review recent advance of AI in earlyscreening, diagnosis, therapy and prognosis of stomachcarcinoma. Especially AI combined with breath screeningearly GC system improved 97.4 % of early GC diagnosisratio, AI model on stomach cancer diagnosis system of salivabiomarkers obtained an overall accuracy of 97.18 %, speci-ficity of 97.44 %, and sensitivity of 96.88 %. We also discussconcept, issues, approaches and challenges of AI applied instomach cancer. This review provides a comprehensive viewand roadmap for readers working in this field, with the aimof pushing application of AI in theranostics of stomachcancer to increase the early discovery ratio and curativeratio of GC patients.

Crossover patterns under meiotic chromosome program

Repairing DNA double-strand breaks(DSBs)with homologous chromosomes as templates is the hallmark of meiosis.The critical outcome of meiotic homologous recombination is crossovers,which ensure faithful chromosome segregation and promote genetic diversity of progenies.Crossover patterns are tightly controlled and exhibit three characteristics:obligatory crossover,crossover interference,and crossover homeostasis.Aberrant crossover patterns are the leading cause of infertility,miscarriage,and congenital disease.Crossover recombination occurs in the context of meiotic chromosomes,and it is tightly integrated with and regulated by meiotic chromosome structure both locally and globally.Meiotic chromosomes are organized in a loop-axis architecture.Diverse evidence shows that chromosome axis length determines crossover frequency.Interestingly,short chromosomes show different crossover patterns compared to long chromosomes.A high frequency of human embryos are aneuploid,primarily derived from female meiosis errors.Dramatically increased aneuploidy in older women is the well-known“maternal age effect.”However,a high frequency of aneuploidy also occurs in young women,derived from crossover maturation inefficiency in human females.In addition,frequency of human aneuploidy also shows other age-dependent alterations.Here,current advances in the understanding of these issues are reviewed,regulation of crossover patterns by meiotic chromosomes are discussed,and issues that remain to be investigated are suggested.

Realization of Oriented and Nanoporous Bismuth Chalcogenide Layers via Topochemical Heteroepitaxy for Flexible Gas Sensors

Most van der Waals two-dimensional(2D)materials without surface dangling bonds show limited surface activities except for their edge sites.Ultrathin Bi_(2)Se_(3),a topological insulator that behaves metal-like under ambient conditions,has been overlooked on its surface activities.Herein,through a topochemical conversion process,ultrathin nanoporous Bi_(2)Se_(3) layers were epitaxially deposited on BiOCl nanosheets with strong electronic coupling,leading to hybrid electronic states with further bandgap narrowing.Such oriented nanoporous Bi_(2)Se_(3) layers possessed largely exposed active edge sites,along with improved surface roughness and film forming ability even on inkjet-printed flexible electrodes.Superior room-temperature NO_(2) sensing performance was achieved compared to other 2D materials under bent conditions.Our work demonstrates that creating nanoscale features in 2D materials through topochemical heteroepitaxy is promising to achieve both favorable electronic properties and surface activity toward practical applications.

Single-Cell Microwell Platform Reveals Circulating Neural Cells as a Clinical Indicator for Patients with Blood-Brain Barrier Breakdown

Central nervous system diseases commonly occur with the destruction of the blood-brain barrier.As a primary cause of morbidity and mortality,stroke remains unpredictable and lacks cellular biomarkers that accurately quantify its occurrence and development.Here,we identify NeuN^(+)/CD45^(−)/DAPI^(+)phenotype nonblood cells in the peripheral blood of mice subjected to middle cerebral artery occlusion(MCAO)and stroke patients.Since NeuN is a specific marker of neural cells,we term these newly identified cells as circulating neural cells(CNCs).We find that the enumeration of CNCs in the blood is significantly associated with the severity of brain damage in MCAO mice(p<0:05).Meanwhile,the number of CNCs is significantly higher in stroke patients than in negative subjects(p<0:0001).These findings suggest that the amount of CNCs in circulation may serve as a clinical indicator for the real-time prognosis and progression monitor of the occurrence and development of ischemic stroke and other nervous system disease.