Research Briefing in 2025

Antibody–lectin chimeras (AbLecs) are an immunotherapy modality designed to bind and block glycans that contribute to immune suppression in cancer. AbLecs enhance antitumor immune responses both in vitro and in vivo, outperforming conventional antibody therapies, including approved cancer drugs.

Scientists have now sequenced more than two million bacterial and archaeal genomes, outstripping the ability to perform gold-standard searches for genes. LexicMap is a new tool that can scan millions of genomes for a gene in minutes, precisely locating mutations. This approach will enable many applications in epidemiology, ecology and evolution.

Achieving uniform, isotropic sub-micrometer-resolution imaging at high speed across large, cleared tissues has been a major challenge for light-sheet microscopy. To address this, we developed a cost-effective system that enables tenfold faster volumetric imaging with isotropic resolution of complex biological organs such as the mouse brain and cochlea.

We engineered chimeric variants of the Arabidopsis thaliana pattern recognition receptor RLP23 by replacing the C-terminal domain from orthologous proteins in crop species. Expression of these chimeric receptors in tomato markedly enhanced broad-spectrum resistance without compromising yield. Similar results in rice and poplar demonstrate the broad applicability of this engineering strategy.

We applied emerging label-free biophysical techniques to map the size, composition and shape of RNA lipid nanoparticles. By linking these physical measurements to gene expression in human T cells and mice, we uncovered structure–activity relationships that guide RNA delivery.

Challenges in somatic variant calling include a lack of long-read variant callers and of publicly available benchmarking datasets. We developed DeepSomatic, a somatic variant caller for short- and long-read technologies, and created seven somatic variant benchmarks derived from cancer cell lines, which we make available as a public database: CASTLE-panel.

Precise control of transgene expression remains a challenge in engineering primary cells for diverse applications. We developed DIAL, a promoter editing framework that transmits transient inputs into stable setpoints of expression in primary cells and human induced pluripotent stem cells, paving the way for predictable programming of gene circuits in therapeutically relevant cells.

Most bacteria cannot be grown in the laboratory, which means that their genetic diversity is hidden to traditional culture-based studies. We combined a new DNA extraction method, long-read sequencing, bioinformatics and chemical synthesis to access the genetic diversity of uncultured soil bacteria and abiotically decode it to discover bioactive small molecules.

A new screen platform named DEFUSE (DEath FUSion Escape) enables high-throughput discovery of small molecule protein degraders. DEFUSE identified SKPer1, a molecule that works by inducing proximity between an oncogenic driver and an E3 ligase, opening new avenues for targeted protein degradation.

Antibody–drug conjugates (ADCs) are promising targeted cancer therapies but have a limited payload scope. Antibody–bottlebrush prodrug conjugates offer modular synthesis and high drug-to-antibody ratios, enabling the use of a broad range of payloads, including lower potency drugs, while performing favorably compared to traditional ADCs in preclinical models.

We developed a universal control system and multitarget optimization framework that enables dynamic and synchronized expression of multiple genes and facilitates the overproduction of specific secondary metabolites in Streptomyces species.

Precision CRISPR–Cas9-mediated genome engineering remains challenging, particularly gene integration and editing in non-dividing cells. We present Pythia, a deep learning solution that forecasts optimal repair templates and enables predictable and accurate genome editing in diverse cellular contexts, both in vivo and in vitro.

A robust, clinically tractable skin metatranscriptomics workflow provides high technical reproducibility of profiles, uniform coverage across genes, and strong enrichment of microbial messenger RNAs across different skin sites. This workflow is useful for identifying active species and microbial functions in vivo for future biomarker discovery.

PepMLM, a protein language model fine-tuned on protein–peptide data, can generate potent, target-specific linear peptides capable of binding to and degrading proteins ranging from cancer receptors to drivers of neurodegeneration and viral proteins, all without requiring protein structural information.

Cells in a tissue influence each other through physical and chemical cues as they differentiate to their final fates and migrate through space. A new technique integrates spatial transcriptomic data with the dynamics of RNA transcription and splicing across an entire tissue to model the directions of cell differentiation and migration.

We developed low-input multiple methylation sequencing (LIME-seq) to detect RNA modifications in plasma cell-free RNA (cfRNA) and identified microbiome-derived RNA modification signatures that can distinguish people with colorectal cancer from those without. We suggest that monitoring the modification levels on cfRNA or other RNA species could aid disease diagnosis and prognosis.

We developed Dual Selective Organ-Targeting Lipid Nanoparticles (Dual SORT LNPs) capable of delivering base editors to multiple organs. Base editor Dual SORT LNPs corrected disease-causing mutations in both the liver and lungs, the primary organs affected in alpha-1 antitrypsin deficiency.

Protein materials are promising drug delivery vehicles, but their use for intracellular protein and nucleic acid cargo delivery has been limited. We have developed self-assembling elastin-like polypeptide (ELP)-based protein nanoparticles that are functionalized to enable complexation and intracellular delivery of biomacromolecular cargo, including gene editors in the form of mRNA, plasmid DNA and ribonucleoproteins.

Proteomics samples of human cancer biopsies were combined to derive an atlas of protein–protein associations for human tissues. Differences between tissues are not strongly driven by gene expression but could, in part, be due to tissue-specific subcellular components and processes.

How modifications to RNA molecules and the proteins they interact with on the cell surface contribute to cancer is largely unknown. Preclinical evidence indicates that cell surface nucleophosmin (NPM1, an RNA-binding protein) is a novel druggable biomarker in acute myeloid leukemia, with potential implications for improving detection and immunotherapy strategies for several cancer types.