Oligonucleotide therapeutics (ONTs) enable precise modulation of gene expression and RNA function through diverse sequence- and structure-dependent mechanisms but face translational challenges in conventional animal models, particularly for human-specific biology. This review focuses on organoids and organ-on-a-chip platforms as emerging human-relevant models within the broader framework of new approach methodologies for oligonucleotide drug development. We summarize major oligonucleotide modalities and biological barriers to cellular uptake and intracellular trafficking, emphasizing hepatic delivery and extrahepatic applications. Representative studies illustrate their use in assessing target engagement, RNA modulation, pharmacological response and safety. We further discuss regulatory considerations, context of use and current limitations. Further development of these models is expected to enhance translational relevance and support the development of ONTs.

Population heterogeneity in disease biology, drug exposure and treatment response is often addressed only after development has progressed, limiting generalizability and increasing late-stage risk. We propose an anticipate-verify-influence framework to integrate clinically relevant variability from research through development. The approach combines diverse human-derived models, real-world data, model-informed drug development and AI/ML to identify drivers of heterogeneity, test their clinical relevance early and translate validated findings into trial design, dosing and patient selection. Rather than pursuing demographic representation alone, the framework emphasizes mechanistic and quantitative understanding of intrinsic and extrinsic determinants of response. Earlier characterization of meaningful heterogeneity could improve development decisions, trial representativeness and evidence generation for patients who are frequently underrepresented.

Hepatocellular carcinoma (HCC) is the most common cancer and a leading cause of death. Multi-kinase inhibitors are vital for treating advanced HCC, yet drug resistance remains a major challenge. The molecular basis of metabolic adaptation to drug resistance is poorly understood. Evidence indicates that metabolic reprogramming, particularly dysregulated cholesterol metabolism, plays a key part in drug resistance. Sterol regulatory element-binding protein 2 (SREBP2) regulates cholesterol synthesis, stabilizes receptor tyrosine kinases (RTKs), promotes lipid raft formation, and reduces ATP-binding cassette transporter subfamily A member 1 (ABCA1) and cholesterol efflux, leading to increased intracellular cholesterol. Y-box binding protein 1 (YBX1), a DNA/RNA-binding protein, induces cancer metastasis and drug resistance by modulating ABC transporters, phosphoinositide 3-kinase (PI3K)/AKT, and lipid metabolism. This review discusses the role of cholesterol metabolism in resistance, focusing on SREBP2 and therapeutic strategies targeting cholesterol.

Cancer vaccines are emerging as a promising approach in immuno-oncology, with the potential to generate tumour-specific and long-lasting immune responses. However, shared-antigen strategies often show limited efficacy because of tumour heterogeneity, immune escape and challenges in identifying immunogenic targets, ultimately limiting progress towards effective immunotherapies. Recent breakthroughs in artificial intelligence (AI) are facilitating a shift towards systematic and data-driven vaccine design, effectively bridging conventional design gaps. AI-driven integration of immunopeptidomics, sequence optimisation and delivery design supports a more cohesive therapeutic pipeline. This review highlights recent advances, key challenges and the scientific and translational considerations shaping next-generation cancer vaccines.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have transformed the management of type 2 diabetes and obesity and are increasingly recognised for their pleiotropic effects beyond glycaemic control. Growing evidence suggests that these agents influence inflammatory, vascular and neuroprotective pathways relevant to ocular disease, creating opportunities for therapeutic repurposing while raising important questions regarding long-term ocular safety. This review crucially synthesises current mechanistic, preclinical and clinical evidence regarding the role of GLP-1 RAs across major ophthalmic conditions. Experimental studies consistently demonstrate anti-inflammatory, antioxidative and neurovascular-protective effects, particularly in diabetic retinopathy, whereas clinical studies suggest a potential benefit yet are limited by heterogeneous study designs and the absence of dedicated ophthalmic endpoints. We also examine emerging safety signals, including reported associations with nonarteritic anterior ischaemic optic neuropathy and neovascular age-related macular degeneration, highlighting the limitations of current observational evidence and the uncertainty surrounding causality. Finally, we discuss the translational potential of GLP-1 RAs in immune-mediated ocular diseases such as noninfectious uveitis and identify key priorities for future research. Because the clinical use of GLP-1 RAs continues to expand, carefully designed prospective studies integrating mechanistic insights with standardised ophthalmic outcomes will be essential to define both their therapeutic potential and long-term ocular safety.

In a selective global biotech funding environment characterized by a 'flight to quality', startups must signal execution readiness to secure capital. Based on a dataset of Japanese drug discovery startups, we examine how management teams' professional and educational backgrounds relate to fundraising performance, finding stage-dependent patterns. Early-stage startups are predominantly academic-led, yet raise less than those led by pharmaceutical veterans. In later stages, CEOs with purely academic backgrounds are associated with lower funding, whereas CEOs with medical degrees or pharmaceutical experience are associated with higher funding. Retaining academic founder-CEOs early may also introduce governance and conflict-of-interest risks. These results are consistent with a view that leadership should evolve as firms mature-incorporating industry professionals early and, potentially, transitioning founder-CEOs before late-stage transitions.

Epigenomic dysregulation is associated with several noncommunicable diseases (NCDs). Chromatin-modifying drugs have the ability to re-establish normal epigenetic regulation, thereby fine-tuning the epigenome. The biochemical and pharmacological mechanisms of these drugs, which target histone lysine and arginine methyltransferases, DNA methyltransferases, histone deacetylases and histone acetyltransferases, histone demethylases and bromodomain and extra-terminal motifs, serve as ideal tools for understanding the modes of action of these epigenetic regulators and the resulting biological events within chromatin. The present review provides an overview of these biochemical mechanisms and some downstream effects of the aforementioned chromatin-modifying drugs.

The catalytic activity of GCN5/p300/CBP-associated factor (PCAF) plays a pivotal role in numerous physiological and pathological conditions, underscoring its potential as a therapeutic target. However, developing clinically viable modulators remains challenging due to highly conserved catalytic domains within the GCN5-related N-acetyltransferases family. Recent advances have shifted the focus from classical catalytic-site inhibitors to noncatalytic-domain inhibitors, improving selectivity and specificity. Emerging approaches, including proteolysis-targeting chimeras, acetylation-targeting chimeras, high-throughput screening and rational drug design, are reshaping the landscape of inhibitor development. This review outlines the structural features, functions and diverse roles of GCN5/PCAF in disease pathology, with an emphasis on inhibitor design strategies. We also propose a framework for inhibitor development that integrates active-site engagement, pharmacophore modelling and function-driven targeting strategies to bridge the gap between early-stage discovery and translational potential.

Precision medicine seeks to individualise care by integrating multimodal biomedical data, yet most deployed clinical artificial intelligence (AI) remains assistive, providing predictions without managing workflows or adapting autonomously. Agentic AI, built on large language models (LLMs), has emerged as a paradigm characterised by autonomy, goal-directed reasoning, memory, planning and tool use. This review synthesises evidence on agentic AI and LLMs applied to precision medicine, encompassing drug discovery, genomics, oncology, rare disease diagnostics and clinical pharmacology. This review also examines architectural components, recent validation milestones and emerging challenges, including hallucination, sociodemographic bias and evolving regulatory frameworks across the FDA, the EU AI Act and the WHO.

Recently, China has rapidly strengthened its drug discovery capabilities. To elucidate the technological strategies underlying China's drug discovery advances, this study analyzes Chinese-origin drug candidates that are in late-stage global development, examining the drug target novelty and differentiation strategy for these candidates. The analysis reveals that Chinese-origin compounds in Phase 3 trials target molecules that have already been addressed by approved drugs more frequently than do compounds originating from other countries. In China's drug discovery, target-combination strategies that simultaneously targeted multiple molecules already validated by approved drugs were frequently used, often enabled by next-generation antibody technologies. Concurrently, the optimization of small molecules to create improved drugs has been actively pursued. The implications of this analysis for strategies to enhance drug discovery capabilities at corporate and national levels are discussed.

Autoimmune diseases arise from breakdown of immune tolerance and are commonly treated with broad immunosuppression that limits efficacy and increases toxicity. For drug discovery, mRNA therapeutics offer a programmable, modular platform to develop antigen-specific and mechanism-driven autoimmune therapies. mRNA-based approaches enable transient, controllable expression of self-antigens, immunoregulatory proteins and transcription factors to induce tolerance, reshape local immune microenvironments and enhance regulatory immune pathways. Preclinical studies across models of multiple sclerosis, type 1 diabetes, lupus, inflammatory bowel disease and rheumatoid arthritis demonstrate proof-of-concept and translational potential. Collectively, these findings position mRNA therapeutics for selective immune modulation while preserving immunity.

The growing emphasis on sustainable healthcare has accelerated the development of biodegradable drug delivery systems (DDS) as environmentally responsible alternatives to conventional polymeric carriers. Natural biopolymers and biodegradable synthetic polymers offer biocompatibility, controlled degradation and the potential to reduce long-term environmental burden when combined with green manufacturing and life-cycle-based design. Recent advances in nanoscale engineering, stimuli-responsive delivery and sustainable synthesis have further enhanced their therapeutic performance. However, challenges, including raw material variability, inconsistent degradation, manufacturing scalability, regulatory standardization and limited life cycle assessment, remain barriers to widespread clinical translation. Addressing these challenges through interdisciplinary innovation, green chemistry and harmonized regulatory frameworks will facilitate the development of high-performance, sustainable DDS that support a more environmentally responsible pharmaceutical industry.

The aryl hydrocarbon receptor (AHR) has been historically excluded from drug development owing to the toxicity of canonical xenobiotic agonists. Drawing on the mechanistic logic of the 6-formylindolo[3,2-b]carbazole (FICZ)-cytochrome P450 1A1 (CYP1A1) axis, we propose a spatio-kinetic design framework built on three principles: optimizing ligand residence time over binding affinity, restricting activation to target tissues through pro-drug strategies, and preserving metabolic feedback to ensure self-terminating signaling. This framework offers a concrete path to AHR modulators that recapitulate the pulse-like physiology of endogenous pathways and thereby unlock the receptor's clinical potential in autoimmunity, cancer, and barrier disorders, while avoiding the chronic activation that has historically defined its toxicity.

Paediatric Investigation Plans (PIPs) are a critical component of the EU's regulatory strategy to ensure that medicines are appropriately studied, developed and authorised for use in children. The legislative scheme for PIPs was established under Regulation (EC) no. 1901/2006, also known as 'Paediatric Regulation'. Paediatric Regulation mandates that all new marketing authorisation applications and line extensions must include data from PIPs unless waivers or deferrals have been granted. This literature review's objective is to explore the 'PIPs, waivers and deferrals' regulatory framework for on- and off-patent drugs and provide a glimpse of the new 'pharma package' upcoming changes.

Cocrystallization has emerged as a versatile and effective strategy to modify physicochemical properties of drugs in molecular solid-state design. However, the selection of suitable cocrystal coformers remains largely guided by empirical knowledge and trial-and-error. In recent years, in silico virtual screening methods, including knowledge-based approaches, physics-based approaches and machine learning, have been recognized as effective tools for addressing these challenges. This review provides a comprehensive overview of the theoretical principles, applications and recent advances in in silico virtual screening methods for predicting cocrystal formation and properties. The advantages and limitations of current methods are crucially analyzed, and promising directions for future research are outlined. These efforts are expected to facilitate more reliable applications of in silico tools in the rational design of pharmaceutical cocrystals.