Lipid Nanoparticle-Mediated Antifungal and Immunomodulatory Therapy for Neuromycoses

Neuromycoses, fungal infections affecting the central nervous system (CNS), cause approximately 112,000 deaths annually, representing 19% of AIDS-related deaths globally. Conventional antifungal drugs are limited by poor blood-brain barrier (BBB) penetration, systemic toxicity, and increasing drug resistance. Lipid nanoparticles (LNPs) have emerged as promising vehicles for enhancing antifungal efficacy while modulating immune responses. Thus, this comprehensive review synthesizes current knowledge on LNPs as vehicles for antifungal immune modulators, including their design principles, drug delivery mechanisms, physiological interactions, translational potential, and roadmap for next-generation precision medicine approaches to treating neuromycoses.

A comprehensive narrative review of original studies on LNP-based approaches for neuromycoses was conducted. The literature was synthesized using a structured evidence table encompassing six studies published between 2019 and 2026, including one randomized clinical trial in adults, one case report, one in vitro study, two animal studies, and one study incorporating both in vitro and in vivo approaches. Original research studies were prioritized, while reviews, commentaries, and editorials were excluded.

This review shows four principal findings: (1) LNP formulations achieved mean fungicidal activity of 0.402 log_{1 0} CFU/mL/day, non-inferior to intravenous amphotericin B, with 18-week survival and reduced toxicity compared to intravenous formulations; (2) LNPs cross the BBB with limited or no systemic toxicity while enabling intracellular trafficking through optimization of lipid composition and surface chemistry; (3) RMT demonstrates high specificity affected by variability in receptor expression, while AMT and TMT operate through distinct mechanisms with their own potential off-target effects; and (4) encapsulation reduces nephrotoxicity and hepatotoxicity compared to free antifungal drugs, with amphotericin B-loaded NLC showing reduced nephrotoxicity in vitro compared to conventional formulations.

These findings highlight the potential of LNP-based antifungal delivery and the need for further clinical validation before broader clinical translation.