Lipid nanoparticles: Composition, formulation, and application.

Lipid nanoparticles (LNPs) are lead non-viral vectors for delivering nucleic acids. LNPs can efficiently encapsulate nucleic acids, protect them from degradation, enhance cellular uptake and induce endosome escape, which show high transfection efficiency and low immunogenicity. In this review, we first introduce the LNP components, highlighting their critical roles in encapsulation, stability, delivery efficiency, and tissue tropism.

Characterization of the extrinsic and intrinsic signatures and therapeutic vulnerability of small cell lung cancers.

Small-cell lung cancer (SCLC), an aggressive neuroendocrine tumor strongly associated with exposure to tobacco carcinogens, is characterized by early dissemination and dismal prognosis with a five-year overall survival of less than 7%. High-frequency gain-of-function mutations in oncogenes are rarely reported, and intratumor heterogeneity (ITH) remains to be determined in SCLC. Here, via multiomics analyses of 314 SCLCs, we found that the ASCL1/MKI67 and ASCL1/CRIP2 clusters accounted for 74.

Coalescing single-cell genomes and transcriptomes to decode breast cancer progression.

Understanding epithelial lineages of breast cancer and genotype-phenotype relationships requires direct measurements of the genome and transcriptome of the same single cells at scale. To achieve this, we developed wellDR-seq, a high-genomic-resolution, high-throughput method to simultaneously profile the genome and transcriptome of thousands of single cells. We profiled 33,646 single cells from 12 estrogen-receptor-positive breast cancers and identified ancestral subclones in multiple patients that showed a luminal hormone-responsive lineage, indicating a potential cell of origin.

Astrocyte Secretome Profiling via Biorthogonal Labeling Unveils Novel Factors Relevant to Neurodegenerative Diseases.

Secreted proteins are key mediators of intercellular communication in multicellular organisms. However, progress in secretomics has been hindered by the lack of effective methods for capturing secreted proteins. Here, we present a two-step secretome enrichment method (tsSEM) that integrates unnatural amino acid labeling with click chemistry-based biorthogonal reaction, enabling robust in vitro secretome profiling in the presence of serum.

Spatio-Temporal Proliferative Heterogeneity of Intra-Organ Endothelial Cells.

Background: Blood vessels play a crucial role in supplying tissues with oxygen and nutrients. The maintenance of normal blood vessel number and integrity requires a continuous supply of new endothelial cells (ECs) through self-replication. While it is established that ECs across different tissues exhibit heterogeneity in molecular signatures and regenerative capacities, the extent of proliferation heterogeneity among ECs within the same organ or tissue remains largely unexplored.

A common structural mechanism for RNA recognition by the SF3B complex in mRNA splicing and export.

The SF3B complex plays a critical role in branch point adenosine recognition during pre-mRNA splicing. Its largest subunit SF3B1 is frequently mutated in cancers, leading to aberrant alternative splicing. Besides its function in pre-mRNA splicing, the SF3B complex also binds mature or intronless mRNAs to facilitate their nuclear export.

Bioactive LDH nanoplatforms for cancer therapy: Advances in modulating programmed cell death.

In recent years, the rapid advancement of nanotechnology and tumor biology has significantly expanded the application of nanomaterials in cancer therapy, particularly through the induction of programmed cell death (PCD) in cancer cells. Layered double hydroxides (LDH), a class of two-dimensional inorganic nanomaterials, have attracted considerable attention due to its tunable structures, excellent biocompatibility, and superior drug delivery capabilities. Emerging research has highlighted the great potential of LDH in modulating various forms of PCD.

Effects of chromosome number reduction on mitotic and meiotic stability in fission yeast.

Background: Genetic information is stored on multiple chromosomes in eukaryotic organisms and is passed on to offspring through cell division. How chromosome number influences cell division and chromosome segregation is not yet understood.

Results: In this study, we use artificial chromosome-fusion fission yeast cells, which contain one or two chromosomes, as models to investigate the effects of a reduced chromosome number on mitosis and meiosis.

Bioengineering Outer-Membrane Vesicles for Vaccine Development: Strategies, Advances, and Perspectives.

Outer-membrane vesicles (OMVs), naturally secreted by Gram-negative bacteria, have gained recognition as a versatile platform for the development of next-generation vaccines. OMVs are essential contributors to bacterial pathogenesis, horizontal gene transfer, cellular communication, the maintenance of bacterial fitness, and quorum sensing. Their intrinsic immunogenicity, adjuvant properties, and scalability establish OMVs as potent tools for combating infectious diseases and cancer.

Artificial chromosome reorganization reveals high plasticity of the budding and fission yeast genomes.

Background: The genome of a eukaryotic cell is usually organized on a set of chromosomes. Recently, karyotype engineering has been applied to various organisms, but whether and to what extent a naturally evolved genome can resist or tolerate massive artificial manipulations remains unexplored.

Results: Using unicellular yeast models of both Saccharomyces cerevisiae and Schizosaccharomyces pombe, we deliberately construct dozens of single-chromosome strains with different chromosome architectures.

RIPK1 S213E mutant suppresses RIPK1-dependent cell death by preventing interactions with RIPK3 and CASP8.

RIPK1 (Receptor-interacting serine/threonine-protein kinase 1) is fundamental in regulating cell proliferation, programmed cell death, and inflammation. Within the TNF (tumor necrosis factor) signaling pathway, the kinase activity of RIPK1 is essential for determining cellular fate, promoting either apoptosis or necroptosis. Mutations disrupting RIPK1 kinase activity significantly impact cellular fate decisions, highlighting its importance in the TNF signaling cascade.

Human iPSC-based breast cancer model identifies S100P-dependent cancer stemness induced by mutation.

Breast cancer is the most common malignancy in females and remains the leading cause of cancer-related deaths for women worldwide. The cellular and molecular basis of breast tumorigenesis is not completely understood partly due to the lack of human research models which simulate the development of breast cancer. Here, we developed a method for generating functional mammary-like cells (MCs) from human-induced pluripotent stem cells (iPSCs).

Pre-rRNA spatial distribution and functional organization of the nucleolus.

The multilayered nucleolus is the primary site of ribosome biogenesis, where successive maturation of small (SSU) and large (LSU) ribosomal subunit precursors occurs. However, the spatiofunctional relationship between pre-rRNA processing and nucleolar substructures and how this adapts to changing cellular physiological demands have remained incompletely understood. Here our spatiotemporal analyses revealed a compartment-specific ribosomal subunit processing in human nucleoli, with SSU processomes maintained in fibrillar centre (FC)-dense fibrillar component (DFC)-periphery dense fibrillar component (PDFC) domains while LSU pre-rRNAs largely transited to PDFC-granular component regions.

Procr chondroprogenitors sense mechanical stimuli to govern articular cartilage maintenance and regeneration.

Protein C receptor (Procr) cells were identified as stem or progenitor cells in multiple adult tissues. However, whether mechanical stimuli fine-tune their activation and differentiation remain unknown. Here, we found rare Procr cells in the superficial layer of tibial articular cartilage and meniscus, which keep replenishing chondrocytes in postnatal knee joints.

Rapid purification and characterization of angiotensin I-converting enzyme from porcine lung.

Angiotensin I-converting enzyme (ACE) is a key target for screening hypertension medicines. However, traditional method for ACE preparation is time-consuming, and commercial ACE is expensive. In this study, a simple and effective method for ACE purification was proposed.

Oxidative stress and Kras mutation in Mist1 cells act in a double-hit manner to drive gastric tumorigenesis.

Oxidative stress is a "double-edged sword" in mediating cellular activities. Here, we report that Mist1 cells are resistant to oxidative-stress-induced cell death and that persistent oxidative stress and Kras mutation act in Knudson's "two-hit" paradigm to promote gastric cancer initiation. Reactive oxygen species (ROS) accumulation causes metaplastic lineage expansion of Mist1 cells, licensing them as a cellular origin of gastric cancer.

Phosphorylation-Dependent Stabilization of Collaborator of ARF (CARF) Suppresses Lymphoma Cell Proliferation.

Uncontrolled cell proliferation drives tumorigenesis and malignant progression, making cell cycle regulation a promising strategy for cancer therapy. Phosphorylation plays pivotal roles in cancer initiation and metastasis by regulating the cancer-related proteins. Identifying key phosphorylation sites is essential for inhibiting tumor cell proliferation and optimizing therapy strategy.

A cohort of mRNAs undergo high-stoichiometry NSUN6-mediated site-specific mC modification.

mRNA modifications are vital in regulating cellular processes. Beyond N6-methyladenosine (mA), most other internal mRNA modifications lack dedicated catalytic machinery and are typically introduced by tRNA-modifying enzymes. The distribution and stoichiometry of these modifications on mRNAs remain debated and require further validation.

Bispecific targeting of 4-1BB and CCR8 boosts antitumor immunity via Ti-Treg depletion and CD8 activation.

Immune checkpoint therapy has transformed cancer treatment, yet efficacy and safety challenges persist. Selectively inhibiting tumor-infiltrating regulatory T cells (Ti-Tregs) while enhancing CD8 T cell function are complementary strategies in cancer immunotherapy. Here, we engineered a bispecific antibody, FRP303, targeting 4-1BB and CCR8, which are co-expressed on a highly immunosuppressive subset of Ti-Tregs.

Mammalian tRNA acetylation determines translation efficiency and tRNA quality control.

Acetylation is a conserved and pivotal RNA modification. Acetylation of tRNA occurs at C12 (acC12) in eukaryotic tRNAs. Yeast acC12 prevents tRNA from rapid tRNA decay (RTD) at higher temperatures.

Positional BMP signaling orchestrates villus length in the small intestine.

The intestinal epithelium undergoes fast turnover, and the villus length in the small intestine gradually decreases from the duodenum to the ileum. However, the underlying mechanisms remain poorly understood. In this study, we investigate the regulatory mechanism underlying the regional disparity of villus length.

Radiotherapy enhances anticancer CD8 T cell responses by cGAMP transfer through LRRC8A/C volume-regulated anion channels.

The volume-regulated anion channels (VRACs) transport osmolytes, neurotransmitters, and cyclic GMP-AMP (cGAMP) across the cell membrane to regulate cell volume and host defense. We report that the leucine-rich repeat-containing 8A/C (LRRC8A/C) VRAC plays a crucial role in immune responses to radiotherapy and chemotherapy for cancer. VRACs transfer cGAMP from irradiated cancer cells to infiltrating CD4 and CD8 T cells, thus enhancing their effector functions.

Mechanism of cytarabine-induced neurotoxicity.

Postmitotic neurons have high levels of methylated cytosine and its oxidized intermediates such as 5-hydroxymethylcytosine. However, the functional relevance of these epigenetic modifications of DNA are poorly understood. Here we show that some cytidine analogues, such as cytarabine, cause DNA double-strand breaks during TET-mediated active 5-methylcytosine demethylation by interrupting TDG-dependent base excision repair.

Tailoring the adjuvanticity of lipid nanoparticles by PEG lipid ratio and phospholipid modifications.

Lipid nanoparticles (LNPs) represent the leading delivery platform for mRNA vaccines with advantageous biocompatibility, scalability, adjuvant activity and often an acceptable safety profile. Here we investigate the physicochemical characteristics and adjuvanticity of four-component LNPs. Previous vaccine studies have demonstrated that altering the ionizable lipid influences the adjuvanticity of an LNP; however, the impact of the polyethylene glycol lipid and phospholipid has received less attention.