REZAFUNGIN NANOCARRIER SYSTEMS FOR IMPROVED CORNEAL PENETRATION AND SUSTAINED OCULAR DELIVERY

Fatema Neherwala*, Avinash Shah

ABSTRACT

Fungal keratitis (FK) remains a leading cause of monocular blindness worldwide, particularly in low- and middle-income countries, with current topical therapies such as natamycin suffering from poor corneal penetration, narrow antifungal spectrum, and rapid precorneal clearance. Rezafungin, a next-generation echinocandin with an extended half-life (>130 hours), enhanced chemical stability, and potent activity against Candida and Aspergillus species, presents a compelling candidate for ophthalmic repurposing. However, its high molecular weight (~1100 Da), amphiphilicity, and susceptibility to efflux transporters (P-gp, BCRP) necessitate advanced formulation strategies to achieve therapeutic corneal concentrations. This manuscript comprehensively reviews nanocarrier-based systems designed to improve rezafungin’s corneal penetration and sustain its ocular delivery. Lipid-based nanocarriers—nanostructured lipid carriers (NLCs), solid lipid nanoparticles (SLNs), and nanoemulsions—enhance mucoadhesion and transcorneal flux by 3- to 5-fold. Polymeric nanoparticles (chitosan, PLGA, hyaluronic acid-functionalized) provide sustained release over 7–14 days and enable CD44-mediated endocytosis. Liposomes and niosomes achieve up to 6-fold enhancement in permeation, with cationic niosomes penetrating deeper into the corneal stroma. Cyclodextrin complexes (HP-β-CD) improve rezafungin solubility 5- to 7-fold, while dendrimers act as molecular shuttles. Hydrogel-based in situ gelling systems (thermoresponsive, pH-sensitive, ion-activated) and mucoadhesive thiolated polymers extend precorneal residence time from minutes to over 6 hours. Ocular inserts and nanoparticle-loaded ointments provide once-daily or once-weekly dosing, with pharmacokinetic studies in rabbit models showing 12.5-fold increases in corneal AUC. Advanced platforms, including cell-penetrating peptide (TAT, penetratin)-conjugated nanoparticles (10- to 15-fold increased intracellular uptake), stimuli-responsive (ROS, pH, MMP) nanocarriers for on-demand release, lipid-polymer hybrid nanoparticles, exosomes, and dissolving microneedles (10- to 50-fold permeability enhancement), represent next-generation strategies. Regulatory challenges—sterilization, scale-up, batch consistency, and preservative toxicity—are discussed, alongside future directions including IVIVC models, combination therapy, and personalized antifungal regimens. Collectively, rezafungin nanocarrier systems hold transformative potential to overcome ocular barriers, drastically reduce dosing frequency, and improve outcomes in fungal keratitis.

Keywords: Fungal keratitis; rezafungin; echinocandin; ocular drug delivery; nanocarriers; corneal penetration; sustained release; lipid nanoparticles.