Reviews & Analysis

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.

The Hippo signalling pathway fulfils a vital role in the regulation of tissue homeostasis and organ development and its dysregulation is associated with several diseases. This Review provides an overview of Hippo pathway signalling and regulation, highlighting its biological functions and role in diseases. Recent advances and future directions in the development of Hippo pathway-targeted therapies, primarily in cancer, are discussed.

Tumour cells undergo profound changes in their metabolism, but targeting these metabolic pathways requires understanding of the impact on immune cells as well as cancer cells. This Review discusses how metabolic pathways in cancer and immune cells shape the tumour microenvironment and describes metabolic modulators and dietary nutrients developed to improve the anticancer immune response.

DNA damage to the somatic genome has been identified as a major cause of ageing. This Perspective provides an overview of current understanding of the role of genome instability in the ageing process and assesses therapeutic strategies targeting the cellular response to DNA damage to delay ageing and prevent associated diseases.

Intrinsically disordered proteins are frequently dysregulated in many diseases, but because of their heterogeneous, highly dynamic structural states they have been considered largely ‘undruggable’ by traditional approaches. This Review proposes that a synergy of advanced experimental and computational approaches will help to overcome this barrier to drug discovery.

The gut microbiome is a key modulator of immunotherapy efficacy. This Review discusses clinical advances in microbiome profiling, recent trials of microbiome-based interventions and the challenges of translating these findings into the clinic. Future directions for optimizing microbiome-targeted therapies in oncology are outlined, including safety, efficacy and patient stratification. 

Neutrophils are abundant in the tumour microenvironment and often correlate with poor prognosis. This Review explores neutrophil subtypes — including those with antitumour activity — their polarization potential and mechanisms influencing tumour progression. Therapeutic targets and signalling pathways are discussed, alongside clinical trials assessing neutrophil-targeted approaches on patient outcomes.

New approach methodologies (NAMs) offer the promise of greater predictivity of potential safety risks of drug candidates, especially for newer types of therapeutics for which animal models alone have limited or no applicability for safety testing. This article identifies four categories of drug candidate for which NAMs are applicable and discusses progress in their use based on case studies from recent projects, as well as initiatives to promote the advancement and use of NAMs for more human-relevant safety assessment.

GLP-1-based therapies represent highly effective treatments for patients with type 2 diabetes and obesity. This Review profiles established and emerging GLP-1-based medicines, focusing on novel GLP-1 receptor agonists and GLP-1-based multi-agonists. Considerations and challenges in the development of GLP-1-based therapies and potential future indications are discussed.

The aryl hydrocarbon receptor (AHR) mediates the toxic effects of environmental pollutants and regulates innate and adaptive immune responses. This Review discusses how, in the past, AHR activation was avoided during drug development, but now the AHR is being targeted for treating inflammation, cancer and infectious diseases.

An increasing array of biomarkers available in blood, cerebrospinal fluid and through imaging are providing valuable proxies of disease processes in neurodegenerative disorders (NDDs). In their Review, Cummings and co-authors discuss the implementation of biomarkers in clinical trials across various NDDs, focusing on the context of use, to help expedite and de-risk drug development.