Lipid-based nanocarriers for antifungal drug delivery

Fungal diseases constitute a rapidly escalating global health threat, causing an estimated 1.5-2 million deaths annually and affecting more than one billion individuals worldwide, particularly immunocompromised patient populations. The increasing incidence of severe systemic infections, severely limited therapeutic options, prolonged treatment regimens, and the rapid emergence of antimycotic resistance collectively underscore the urgent clinical need for innovative treatment strategies. Consequently, the World Health Organization (WHO) has highlighted sustainable investment in antifungal research and the targeted development of novel therapeutics as a primary global priority. Nanotechnology-based drug delivery systems, particularly advanced lipid-based nanocarriers, offer highly promising solutions to overcome current therapeutic limitations. Sophisticated vesicular systems have successfully demonstrated improved target-site accumulation, highly controlled drug release, enhanced tissue penetration (including deep ocular and cutaneous applications), and drastically reduced systemic toxicity in both preclinical and selected clinical settings. Furthermore, PEGylated and ligand-functionalized liposomes, such as DC-SIGN targeted amphotericin B formulations, significantly improve pathogen-specific binding and overall antifungal activity in rigorous experimental models. Emerging formulation strategies, including pH-responsive stealth liposomes and stimuli-sensitive systems adapted directly from oncological applications, suggest immense potential for maximizing antifungal selectivity and clinical efficacy. Additionally, advanced liposome-in-hydrogel hybrid matrices enable sustained therapeutic release, remarkably enhancing formulation stability while minimizing off-target systemic exposure. This comprehensive review provides an integrative analysis of nanostructured lipid carriers in antifungal therapy, detailing fundamental mechanistic principles, advanced formulation strategies, scalable preparation methodologies, and diverse clinical applications. Particular emphasis is strategically placed on highly deformable liposomal platforms explicitly engineered to overcome the structural limitations of conventional delivery systems. Ultimately, successfully bridging the formidable translational gap between experimental benchtop innovation and routine clinical implementation requires harmonized regulatory frameworks, scalable and reproducible manufacturing protocols, rigorous quality control, and substantially enhanced public and private sector collaboration. By synthesizing mechanistic pharmacological insights with realistic translational and regulatory perspectives, this work aims to advance the fundamental understanding of lipid-based antifungal delivery platforms and directly support the development of highly effective, clinically viable therapeutic approaches.