Lipid nanoparticle-based drug delivery for invasive fungal infections: engineering strategies, therapeutic advances, clinical translation, and future perspectives

Abstract

Invasive fungal infections (IFIs) remain a major cause of morbidity and mortality among immunocompromised patients despite the availability of multiple antifungal agents. Their clinical management is frequently limited by poor aqueous solubility, inadequate tissue penetration, systemic toxicity, unfavorable pharmacokinetics, antifungal resistance, and biofilm-associated persistence. Lipid nanoparticle (LNP)-based drug delivery systems have emerged as promising platforms to overcome these limitations by improving drug stability, biodistribution, intracellular delivery, controlled release, and targeted accumulation at infected tissues. Among clinically established formulations, liposomal amphotericin B (AmBisome®) exemplifies successful clinical translation, maintaining antifungal efficacy while reducing the risk of clinically significant nephrotoxicity by approximately 51% (RR ≈ 0.49) compared with conventional amphotericin B. Building upon this success, numerous preclinical LNP platforms have demonstrated enhanced macrophage targeting, improved biofilm penetration, prolonged circulation, and superior delivery of polyenes, azoles, echinocandins, and emerging antifungal agents. This review critically evaluates advances in LNP formulation engineering, pathogen-specific therapeutic applications, biological mechanisms, manufacturing scalability, Quality-by-Design (QbD), regulatory expectations, patent landscape, and the principal barriers limiting successful clinical translation. Emerging opportunities, including ligand-directed targeting, stimuli-responsive lipid nanocarriers, and evidence-based integration of artificial intelligence for formulation optimization, are discussed within the context of realistic clinical development. Unlike previous reviews, this review integrates pharmaceutical engineering, comparative formulation assessment, translational readiness, and regulatory perspectives into a unified evidence-based framework that provides a practical roadmap for accelerating the clinical translation of next-generation antifungal lipid nanomedicines. Not applicable