Recent Advances and Challenges in Addressing Drug-induced Liver Injury (DILI): Mechanisms and Nanocarrier Solutions.

Abstract

Introduction: Drug-Induced Liver Injury (DILI) is a leading cause of drug attrition, postmarketing withdrawals, and acute liver failure. It presents a major barrier to the safe development of new therapeutics, particularly due to its unpredictable pathogenesis and the lack of reliable preclinical models. Current diagnostic tools, primarily reliant on liver enzyme elevations, lack specificity and sensitivity, especially in cases of idiosyncratic DILI. With increasing awareness of these limitations, there is growing interest in integrating advanced delivery systems, predictive models, and pharmacogenomic screening into drug safety assessment.

Methodology: This review systematically synthesizes peer-reviewed literature identified through Scopus, PubMed, and Web of Science, published over the past two decades. The review focuses on mechanistic insights into Drug-Induced Liver Injury (DILI), diagnostic challenges, and recent advances in nanocarrier-based drug delivery and predictive strategies. Relevant literature was identified using search terms such as "DILI," "nanocarriers," "pharmacogenomics," and "liver toxicity.

Results: Recent findings underline the complex etiology of DILI, involving mitochondrial dysfunction, reactive metabolite accumulation, and immune-mediated responses. Nanoparticle-based drug formulations, including liposomes, polymeric nanoparticles, and dendritic systems, demonstrate promise in reducing hepatic exposure and delivering hepatoprotective co-agents. Innovations such as liver-on-a-chip models and AI-driven predictive tools offer enhanced screening potential. Pharmacogenomic profiling is increasingly recognized for enabling individualized risk assessment.

Discussion: The integration of nanotechnology with predictive toxicology and pharmacogenomics represents a significant advancement in DILI prevention and early detection. These emerging approaches address many limitations of conventional preclinical models by providing more physiologically relevant systems and supporting personalized therapeutic strategies. However, challenges related to clinical translation, regulatory acceptance, cost, and validation across diverse populations remain to be addressed.

Conclusion: Advances in nanocarrier-based drug delivery, pharmacogenomics, and human-relevant predictive models have the potential to transform DILI risk assessment and improve drug safety. Continued interdisciplinary research, large-scale clinical validation, and regulatory integration are essential for translating these innovations into routine pharmaceutical development and clinical practice.