Tetrahedral framework nucleic acids (tFNA) are specialised three-dimensional DNA nanostructures with precise self-assembly, structural rigidity, programmability, and excellent biocompatibility. Their resistance to enzymatic degradation is enabled by their unique tetrahedral geometry, which also facilitates efficient cellular internalisation without the need for transfection agents. Thus, establishing tFNA as both a versatile regulator and a nanocarrier. Healing in orthopaedics is often stalled by limited tissue regeneration, unpredictable inflammation and infection, and suboptimal drug localisation within complex microenvironments. This review summarises recent advances in the application of tFNA across key orthopaedic domains, including bone and cartilage regeneration, angiogenesis, immunomodulation, anti-microbial therapy, and bone cancer treatment. tFNA have been shown to enhance osteogenic and chondrogenic differentiation of multiple mesenchymal stem cell populations by indirectly activating the Wnt/β-catenin and PI3K/AKT pathways. When functionalised with peptides, small molecules, nucleic acids, or natural compounds, tFNA promote angiogenesis, suppress oxidative stress, inhibit inflammatory and pyroptotic signalling, and restore extracellular matrix homeostasis in degenerative joint diseases. Furthermore, integration of tFNA with antibiotics, antimicrobial peptides, hydrogels, and implant surfaces demonstrates promising efficacy in combating orthopaedic infections and biofilm formation while supporting tissue regeneration. Emerging tFNA-based delivery systems for osteosarcoma therapy further illustrate their translational versatility. Despite these encouraging findings, several challenges hinder clinical translation: large-scale synthesis, long-term biosafety, immune responses, pharmacokinetics, and controlled degradation within mechanically and biologically complex orthopaedic environments. Interdisciplinary research and optimisation are ongoing to advance tFNA-based platforms toward safe, effective, and personalised nanotherapeutic strategies in orthopaedics. These developments may ultimately redefine precision therapies for the global management of musculoskeletal diseases.

Drug-induced liver injury remains a principal trigger of acute hepatic failure, late-stage drug attrition, and post-marketing withdrawal, reflecting persistent limitations in mechanistic prediction and translational safety assessment. Owing to its central role in xenobiotic biotransformation, the liver is highly vulnerable to metabolic bioactivation and reactive intermediate formation. This review presents a metabolism-centered; systems level framework that integrates Phase-I and Phase-II enzymatic processes with downstream cellular stress responses governing hepatocellular fate. Cytochrome 450-mediated oxidation and subsequent conjugative pathways determine the balance between detoxification and electrophilic burden; disruption of this equilibrium initiates oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, bile-acid transport impairment, immune-inflammatory activation, and regulated cell death. Emphasis is placed on the dynamic crosstalk among these pathways, which explains interindividual variability, idiosyncratic susceptibility and preclinical-clinical discordance. Emerging insights from network toxicology, transcriptomics, metabolomics and computational modelling have enhanced mechanistic resolution beyond conventional biomarkers. Concurrently, advanced experimental systems including three-dimensional hepatic cultures, organoids, micro-physiological liver-on-chip platforms, humanized animal models and integrative in vitro-in silico approaches are improving translational fidelity. Collectively, this synthesis advances a cohesive mechanistic perspective and highlights integrative strategies to strengthen early risk stratification, mechanistically informed evaluation and predictive safety assessment in drug development.

This study summarizes the chemical features, pharmacological effects, pharmacokinetic profiles, and current limitations arising from the limited natural distribution of Jujuboside A (JuA). Since demand for JuA is increasing while natural resources are scarce, our review focuses is its biosynthetic pathway and production challenges. Recent advances and perspectives on alternatives for production are also discussed, such as directed glycosylation based on structurally related homologs, metabolic pathway regulation of sour jujuba (Ziziphus jujububa var. spinosa (Bunge) Hu ex H.F.Chou), microbial cell factory development, and plant callus culture. This review summarizes the pharmacological activities, pharmacokinetics, and biosynthesis of JuA, and discusses current limitations and potential production strategies. Collectively, these insights highlight the pharmacological potential of JuA and provide a theoretical basis for future mechanistic studies and sustainable large-scale production.

Branched-chain amino acids (BCAAs)-encompassing leucine, isoleucine, and valine-constitute a class of essential amino acids indispensable for protein synthesis and a myriad of metabolic functions. Beyond their canonical roles as substrates, BCAAs are now recognised as potent signalling molecules and key regulators of immunometabolism. They exert pleiotropic effects and demonstrate a profound capacity to modulate inflammatory responses. Inflammation, an intricate biological response to harmful stimuli, is a pathogenic driver underpinning the initiation and exacerbation of numerous chronic and acute diseases. This review critically synthesises the scientific literature, systematically examining the therapeutic potential of BCAAs in mitigating inflammation-related pathologies. We delve into the mechanistic intricacies through which BCAAs exert their anti-inflammatory and immunomodulatory actions. A thorough comprehension of these mechanisms is not merely an academic exercise but a crucial prerequisite for developing effective pharmacotherapies and precision nutrition approaches, ultimately forging new paradigms for the prophylaxis and clinical management of diseases with an inflammatory component.

In the article titled "Nanocochleates in Clinical Trials: A Review of Current Status, Challenges, and Future Directions", published in Current Drug Metabolism, 2025, 26(6), 390-401 [1], the in-text citation of references [100, 101] was inadvertently included in Table 2 of the original version of the manuscript. The original article can be found online at: https://www.eurekaselect.com/article/150830.

Impairment or irreversible loss of bone tissue function remains a prevalent clinical challenge, frequently compounded by donor scarcity, perioperative infection, and immune-mediated rejection, which collectively constrain therapeutic success rates. Novel functional nanomaterials based on nucleic acids-endowed with superior biocompatibility, predictable biodegradability, negligible systemic toxicity, and an abundance of programmable modification sites-have emerged as versatile platforms in bone tissue engineering. Currently, these materials are principally exploited across four interrelated domains: sustained release, bone targeting, scaffold materials for bone regeneration, and bioimaging, all aimed at orchestrating efficient bone regeneration. Recent mechanistic investigations into nano-bio interactions reveal that autophagy, a conserved catabolic pathway in eukaryotes that maintains energetic and metabolic homeostasis, critically governs skeletal repair by directing the timely degradation of intracellular cargo and the turnover of damaged organelles. Through direct modulation of osteoclast and osteoblast differentiation, autophagy fine-tunes the coupled process of bone remodeling. Concurrently, it shapes the regenerative milieu by reprogramming immune cell responses. Consequently, targeted modulation of autophagy represents a rational and promising strategy through which nucleic acid nanomaterials can accelerate bone regeneration. This review synthesizes current knowledge on the contributions of nucleic acid nanomaterials to bone healing, delineates the regulatory functions of autophagy in skeletal regeneration, and explains how these nanomaterials exploit autophagy as a mechanistic lever to enhance bone repair.

Polyunsaturated Fatty Acids (PUFAs) are essential components of the human diet and physiology. Their biotransformation generates bioactive metabolites with regulatory functions in inflammation, vascular homeostasis, and tumor progression. Among these, arachidonic acid derivatives mediated by cytochrome P450 (CYP) enzymes, such as Epoxyeicosatrienoic acids (EETs) and Hydroxyeicosatetraenoic acids (HETEs), have emerged as key modulators of angiogenesis in the hypoxic tumor microenvironment. This review addresses the metabolic mechanisms that regulate the conversion of PUFAs by the CYP2C, CYP2J, and CYP4A/F families, emphasizing their role in activating signaling pathways such as VEGF/VEGFR and HIF-1, which impact cell proliferation, migration, and survival. Likewise, the therapeutic implications of modulating these PUFAs-metabolizing enzymes are analyzed, including the potential of EETs and 20-HETE analogs as pharmacological targets, with a view to developing new strategies for hypoxia-induced angiogenesis in cancer cells.