Aneuploid embryonic stem cells drive teratoma metastasis.

Aneuploidy, a deviation of the chromosome number from euploidy, is one of the hallmarks of cancer. High levels of aneuploidy are generally correlated with metastasis and poor prognosis in cancer patients. However, the causality of aneuploidy in cancer metastasis remains to be explored. Here we demonstrate that teratomas derived from aneuploid murine embryonic stem cells (ESCs), but not from isogenic diploid ESCs, disseminated to multiple organs, for which no additional copy number variations were required. Notably, no cancer driver gene mutations were identified in any metastases. Aneuploid circulating teratoma cells were successfully isolated from peripheral blood and showed high capacities for migration and organ colonization. Single-cell RNA sequencing of aneuploid primary teratomas and metastases identified a unique cell population with high stemness that was absent in diploid ESCs-derived teratomas. Further investigation revealed that aneuploid cells displayed decreased proteasome activity and overactivated endoplasmic reticulum (ER) stress during differentiation, thereby restricting the degradation of proteins produced from extra chromosomes in the ESC state and causing differentiation deficiencies. Noticeably, both proteasome activator Oleuropein and ER stress inhibitor 4-PBA can effectively inhibit aneuploid teratoma metastasis.

Calcium Tungstate Microgel Enhances the Delivery and Colonization of Probiotics during Colitis via Intestinal Ecological Niche Occupancy.

The effective delivery and colonization of probiotics are recommended for therapeutic interventions during colitis, the efficacy of which is hampered by abnormally colonized Enterobacteriaceae at pathological sites. To improve the delivery and colonization of probiotics, a calcium tungstate microgel (CTM)-based oral probiotic delivery system is proposed herein. CTM can selectively disrupt the ecological niche occupied by abnormally expanded Enterobacteriaceae during colitis to facilitate probiotic colonization. In addition, the calcium-binding protein, calprotectin, which is highly expressed in colitis, efficiently extracts calcium from CTM and releases tungsten to inhibit Enterobacteriaceae by displacing molybdenum in the molybdenum enzyme, without affecting the delivered probiotics. Moreover, CTM demonstrated resistance to the harsh environment of the gastrointestinal (GI) tract and to intestinal adhesion. The synergistic reduction of Enterobacteriaceae by 45 times and the increase in probiotic colonization by 25 times, therefore, result in a remarkable treatment for colitis, including restoration of colonic length, effective downregulation of the inflammatory response, restoration of the damaged mucosal barrier, and restoration of gut microbiome homeostasis.

Bionic Regulators Break the Ecological Niche of Pathogenic Bacteria for Modulating Dysregulated Microbiome in Colitis.

Therapeutic approaches that reprogram the gut microbiome are promising strategies to alleviate and cure inflammatory bowel disease (IBD). However, abnormal expansion of Escherichia coli during inflammation can promote pathogenic bacteria occupying ecological niches to resist reprogramming of the microbiome. Herein, a bionic regulator (CaWO4 @YCW) is developed to efficiently and precisely regulate the gut microbiome by specifically suppressing the abnormal expansion of E. coli during colitis and boosting probiotic growth. Inspired by the binding of E. coli strains to the mannose-rich yeast cell wall (YCW), YCW is chosen as the bionic shell to encapsulate CaWO4 . It is demonstrated that the YCW shell endows CaWO4 with superior resistance to the harsh environment of the gastrointestinal tract and adheres to the abnormally expanded E. coli in colitis, specifically as a positioner. Notably, the high expression of calprotectin at the colitis site triggers the release of tungsten ions through calcium deprivation in CaWO4 , thus inhibiting E. coli growth by replacing molybdenum in the molybdopterin cofactor. Moreover, YCW functions as a prebiotic and promotes probiotic growth. Consequently, CaWO4 @YCW can efficiently and precisely reprogram the gut microbiome by eliminating pathogenic bacteria and providing prebiotics, resulting in an extraordinary therapeutic advantage for DSS-induced colitis.

An Intracellular Self-Assembly-Driven Uninterrupted ROS Generator Augments 5-Aminolevulinic-Acid-Based Tumor Therapy.

Free radical therapy based on 5-aminolevulinic acid (ALA, a precursor of the photosensitizer protoporphyrin IX (PpIX)) has been approved by the US Food and Drug Administration for clinical tumor treatment. However, PpIX can be quickly converted into photoinactive heme, leading to unexpectedly paused production of free radicals and severely hindering its therapeutic benefits. Here, inspired by the natural biotransformation of ALA (ALA-PpIX-heme), an uninterrupted reactive oxygen species generator (URG) that converts useless heme to peroxidase mimics via intracellular self-assembly is developed. The URG is prepared by enwrapping ALA-loaded polyamide-amine dendrimers in red blood cell membrane vesicles with a further surface modification of G-quadruplex-structured AS1411. The URGs realize "1 O2 -•OH" uninterrupted generation through "recycling waste" in two steps: i) PpIX generates 1 O2 under laser irradiation; and ii) the photoinactive metabolite heme self-assembled with AS1411 to catalyze H2 O2 conversion into •OH. Interestingly, the specific generation of 1 O2 in mitochondria and •OH in nuclei further augments the free-radical-induced damage. It is demonstrated that URG can continuously produce free radicals for 6 h postirradiation, and shows 3.3-times more than that of the nonassembly group, achieving nearly 80% regression of tumors in vivo.

Engineering CXCL12 Biomimetic Decoy-Integrated Versatile Immunosuppressive Nanoparticle for Ischemic Stroke Therapy with Management of Overactivated Brain Immune Microenvironment.

Following ischemic stroke, brain-resident activated microglia and peripherally infiltrated inflammatory cells create a complicated and overactivated brain immune microenvironment, which causes neuron death and dramatically hinders neurological functional recovery. Herein, an engineering CXCL12 biomimetic decoy-integrated versatile immunosuppressive nanoparticle (VIN) for management of the overactivated brain immune microenvironment is reported. The shell of VIN (membrane of CXCR4 overexpressed mesenchymal stem cells), can not only improve the homing of nanoparticles to the cerebral ischemic lesions, but also efficiently adsorb and neutralize CXCL12 to cut off infiltration of peripheral-neutrophils and mononuclear macrophages. The loaded A151 (cGAS inhibitor, telomerase repeat sequences) can inhibit cGAS-STING pathway in microglia, leading to microglia polarization toward an anti-inflammatory M2-like phenotype. Interestingly, A151 can be efficiently loaded onto the polydopamine nanospheres (PDA, the core of VIN) through the bridge of Zn2+ . In the inflammatory site, PDA is oxidized by reactive oxygen species (ROS), with the disappearance of Zn2+ complexation effect, and then A151 realizes a controlled release. In a model of rat ischemic stroke, VIN integrates inflammation tropism, peripherally inflammatory cells filtrate, brain-resident activated microglia polarization, as well as, ROS scavenging, exerting outstanding therapeutic effects on ameliorating the mortality, reducing the infarct volume, and protecting neurogenic functions of neurons.