Nanotoxicology of Pharmaceutical Nanocarriers: Molecular Mechanisms, Safety Assessment, Regulatory Challenges and Future Perspectives: A Comprehensive Review
Authors
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Amar M. Raval
Department of Pharmaceutics, Sharda School of Pharmacy, Pethapur, Gandhinagar, Gujarat Technological University, Ahmedabad, Gujarat, India
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Kajal M. Doshi
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Astha Suthar
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Divyaben Rajendrakumar Shah
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Vidhi Mehra
Keywords:
Drug delivery systems, nanomedicine, nanotoxicology, pharmaceutical nanocarriers, regulatory toxicology, safety assessmentAbstract
Pharmaceutical nanocarriers have revolutionized drug delivery by enhancing drug solubility, improving bioavailability, enabling targeted delivery and reducing systemic toxicity. Nanocarrier platforms, including liposomes, polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, dendrimers, metallic nanoparticles and other nanoscale delivery systems, have demonstrated considerable therapeutic potential across a broad spectrum of diseases, including cancer, infectious, cardiovascular, neurological and inflammatory disorders. Despite these advances, increasing evidence indicates that the unique physicochemical characteristics of nanocarriers, including particle size, morphology, surface charge, composition and surface functionalization, may trigger unintended biological interactions and adverse toxicological responses. Consequently, comprehensive nanotoxicological evaluation has become a fundamental prerequisite for the safe development, regulatory approval and clinical translation of nanomedicines. This review critically examines the molecular mechanisms underlying nanocarrier-induced toxicity, summarizes current <i>in vitro</i>, <i>in vivo</i> and emerging alternative approaches for nanotoxicity assessment, evaluates the influence of physicochemical properties on biological safety and discusses current regulatory frameworks, existing challenges and future perspectives for the safe and sustainable development of pharmaceutical nanocarriers. A comprehensive literature review was conducted using peer-reviewed publications retrieved from PubMed, Scopus, Web of Science, Embase and Google Scholar. Relevant studies published primarily between 2010 and 2026 were identified using predefined search terms related to nanotoxicology, pharmaceutical nanocarriers, drug delivery systems, safety assessment, regulatory toxicology, oxidative stress, immunotoxicity and nanomedicine. Original research articles, systematic reviews, meta-analyses, regulatory guidance documents and authoritative reports were critically appraised and synthesized to provide a comprehensive overview of current knowledge. Current evidence indicates that nanotoxicity results from complex interactions between nanocarrier physicochemical properties and biological systems. Oxidative stress, excessive reactive oxygen species generation, mitochondrial dysfunction, lysosomal destabilization, DNA damage, inflammation, apoptosis, autophagy, ferroptosis and immune dysregulation have been identified as the principal mechanisms underlying nanocarrier-induced toxicity. These molecular events may lead to organ-specific adverse effects involving the liver, kidneys, lungs, cardiovascular system, nervous system and reproductive organs, with their severity influenced by nanocarrier composition, particle characteristics, dose, exposure duration and route of administration. Emerging technologies, including three-dimensional cell culture models, organ-on-a-chip platforms, high-content imaging, multi-omics approaches and artificial intelligence-driven predictive toxicology, are enhancing the mechanistic understanding, predictive accuracy and translational relevance of nanotoxicity assessment. Nevertheless, significant challenges remain, including the lack of standardized testing methodologies, limited interlaboratory reproducibility, insufficient long-term safety data and incomplete global regulatory harmonization. Pharmaceutical nanocarriers represent a cornerstone of precision medicine; however, their successful clinical translation requires rigorous, standardized and mechanism-based safety evaluation. Integrating mechanistic nanotoxicology, advanced predictive technologies, safe-by-design principles and internationally harmonized regulatory frameworks will be critical for maximizing therapeutic efficacy while minimizing potential risks. Continued interdisciplinary collaboration, technological innovation and evidence-based regulatory development are expected to accelerate the safe and sustainable advancement of next-generation nanomedicines.References
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Copyright (c) 2026 Amar M. Raval, Kajal M. Doshi, Astha Suthar, Divyaben Rajendrakumar Shah, Vidhi Mehra
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