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• Drug solubility remains a central limitation affecting bioavailability and clinical efficacy. • Nanocrystals and nanocarriers enable precise control of size and interfacial properties. • Lipid, polymeric, and hybrid systems markedly enhance dissolution and absorption. • Nanoscale encapsulation improves physicochemical stability and biological performance. • Manufacturing scalability, safety, and regulatory alignment remain key challenges. Drug solubility remains one of the most persistent bottlenecks in modern pharmacotherapy, directly shaping oral absorption, systemic exposure, and ultimately clinical success. A significant proportion of newly developed drug candidates exhibit hydrophobicity, resulting in suboptimal dissolution, dose escalation, and heightened toxicity risks. Recent advances in nanotechnology have introduced transformative strategies to address these limitations, offering precise control over particle architecture, surface chemistry, and drug carrier interactions. This review provides a comprehensive and forward-looking examination of emerging nanotechnological platforms, including nanocrystals, lipid-based carriers, polymeric nanoparticles, and hybrid nanostructures, that are redefining solubility enhancement and bioavailability optimization. Key mechanistic principles such as nanoscale size engineering, interface modification, and encapsulation-driven solubilization are critically discussed to illuminate how these systems improve physicochemical and biological performance. Special emphasis is placed on the expanding applications of nanocarriers in oral, transdermal, pulmonary, and tumour-targeted drug delivery, underscoring their adaptability across therapeutic modalities. Despite remarkable progress, challenges in large-scale manufacturing, long-term safety assessment, and regulatory harmonization persist. By synthesizing current advances and unresolved barriers. This review provides a comprehensive and detailed examination of emerging nanotechnological platforms such as nanocrystals, lipid-based carriers, polymeric nanoparticles, and hybrid nanostructures that are redefining solubility enhancement and bioavailability optimization. Key mechanism principles such as nanoscale size engineering, interface modification, and encapsulation govern solubilization and are discussed to show how these systems improve physicochemical and biological performance.
Singh et al. (Sat,) studied this question.