Reviews & Analysis

Neuroimmune interactions shape neurodegenerative disease progression. This Review examines how microglia integrate signals from central and peripheral immune cells, outlines emerging therapeutic targets beyond core pathology, and discusses the growing need for immune-based biomarkers in Alzheimer’s disease and related disorders.

Extrachromosomal DNA (ecDNA) drives oncogene amplification, tumour evolution and therapy resistance across cancers. This Review summarizes advances in ecDNA biology, highlights emerging therapeutic vulnerabilities and outlines strategies to improve ecDNA detection and translate ecDNA-targeted approaches from bench to bedside.

The blood–brain barrier (BBB) is a dynamic interface that tightly regulates the transport of substances from the blood into the brain. BBB dysfunction can occur with ageing and is a hallmark of many major diseases but is underappreciated as a therapeutic target. Here, Searson and Banks review studies on BBB repair and rejuvenation, highlighting common mechanisms across disorders and potential strategies for pharmacological intervention.

Following on from its success in eradicating malignant B cells in cancer, chimeric antigen receptor (CAR) T cell therapy has been extended to treat autoimmune diseases. This Review discusses the preclinical studies and ongoing clinical trials of CAR T cells in autoimmune disorders, highlighting future opportunities and challenges.

For over 70 years, almost every drug approved for schizophrenia has modulated dopamine signalling, thus only addressing some symptoms and having notable side effects. Here, Coyle and Paul discuss drugs with promising new mechanisms under development for schizophrenia, including those targeting glutamatergic and cholinergic signalling.

The Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway mediates cellular responses to cytokines and growth factors, and its dysregulation plays a role in various disorders including autoimmune diseases, cancers and neurodegenerative disorders. This Review provides an overview of JAK–STAT signalling and discusses current and emerging strategies for therapeutic intervention, highlighting key challenges and new indications.

Epigenetic editing has emerged as a powerful hit-and-run approach to precise modification of gene expression without altering the underlying DNA sequence. This Review explores the therapeutic potential of epigenetic editing, highlights tools and concepts, assesses challenges and considerations, discusses in vivo studies and examines approaches and agents entering clinical development.

Human organoids provide physiologically relevant, 3D models for studying disease mechanisms, drug efficacy and toxicity. This Review examines organoid generation methods, applications in preclinical drug discovery, and the regulatory and practical challenges that must be addressed for their integration into development pipelines.

Induced proximity modalities encompass monovalent and bifunctional agents, such as molecular glues and proteolysis-targeting chimeras, that induce an interaction between biomolecules to functionally modulate the target. This Review highlights seminal discoveries in the field, surveys the various modalities and discusses novel approaches to control cellular processes beyond protein degradation.

Quantitative systems toxicology (QST) models have the potential to increase confidence in the safety assessment of drug candidates and to inform project progression decisions. This article overviews the fundamentals of constructing and using QST models, presents the state-of-the-art for models of cardiovascular, gastrointestinal, hepatic and renal toxicities, and it provides recommendations for their application in drug discovery and development.

In vivo chimeric antigen receptor (CAR)-T cell engineering uses targeted delivery systems to generate CAR-T cells directly in patients, bypassing ex vivo manufacturing. This Review examines emerging viral and lipid nanoparticle platforms, early clinical proof of concept and potential applications beyond cancer.

Chronic obstructive pulmonary disease (COPD) is a progressive and severe respiratory disease featuring airway obstruction and recurrent exacerbations, driven by a complex network of inflammatory processes. In their Review, Agusti and co-authors appraise drugs in development for COPD including recently approved antibodies targeting IL-4 and IL-5 signalling. They discuss opportunities to improve the success of future interventions, including considerations to optimize clinical trial design.

RNA can be chemically modified by enzymes such as methyltransferases to regulate RNA metabolism, gene expression and other biological processes. This Review mainly focuses on the disease-relevant N⁶-methyladenosine RNA modification pathway and discusses efforts to therapeutically target N⁶-methyladenosine writer, eraser and reader proteins.

The potential of microsystem technologies to accelerate the development and clinical translation of immunotherapies is now being realized. This Review discusses recent advances in microsystem technologies, illustrating how their application can address key challenges related to the efficacy, toxicity, predictability and affordability of immunotherapeutics. Future directions and ongoing challenges facing the clinical translation of these technologies are discussed.  

This Review outlines recent advances in synthetic lethality, from CRISPR-based discovery and machine learning-guided prioritization of gene pairs to new phenotypic readouts, highlighting emerging strategies to overcome translational barriers and unlock the therapeutic potential of targeting context-specific genetic dependencies in cancer.

Multispecific drugs are designed to engage two or more entities to exert their pharmacological effect. This Perspective discusses how a new wave of FDA-approved multispecific molecules have been transformative in overcoming barriers to drug development such as toxicity, rapid clearance, undruggable protein features, and functional redundancy.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with diverse clinical manifestations. This Review discusses advances in understanding its immunopathogenesis, the evolution of targeted therapeutic strategies, and emerging approaches to restore immune tolerance. Challenges and opportunities in achieving durable remission or cure in SLE are also explored.

Chemical modification represents an effective strategy to improve the stability, efficiency and specificity of RNA therapeutics, while reducing their immunogenicity. This Review discusses approaches for manufacturing three major categories of RNA — small RNA, translatable RNA and CRISPR guide RNA — and assesses chemical modifications being applied to their broad therapeutic applications. Clinical examples and potential future opportunities are discussed.

CRISPR-based technologies provide a diverse set of tools to correct pathogenic mutations. This Review describes the promise and the challenges of genome editing therapeutic strategies involving nucleases, base editors and prime editors for patients with inherited haematological disorders.

Medicinal chemistry optimizations in the progression from hit to lead to drug candidate affect properties of small-molecule drugs such as their molecular weight and lipophilicity. This Perspective analyses the properties of orally administered small-molecule drug candidates reported in the period 2015–2022 and their corresponding hit and lead compounds, and compares them with the properties of drug candidates identified between 2000 and 2010 and their hits and leads, with the aim of improving understanding of the evolution of hit finding and optimization strategies.