Mangifera indica phytochemical enriched ZnO-Amphotericin B Nanoconjugates: Enhanced hydrophilicity, reduced toxicity and pH-sensitive release for targeted anti-Candida therapy

Amphotericin B (AmB) faces limitations in antifungal applications due to toxicity and poor solubility. This study developed AmB conjugate with green-synthesized zinc oxide nanoparticles (gZnONPs) using Mangifera indica leaf extract (MLE) to enhance pH sensitivity and hydrophilicity. FTIR analysis confirmed AmB conjugation and MLE phytocore on the surface of the gZnONPs, while UV–Vis spectroscopy showed a red shift from 362 to 394 nm after AmB conjugation, indicating successful binding. The conjugate showed increased solubility from 0.31 to 125 µg/mL and enhanced hydrophilicity (contact angle reduced from 53° to 34°). The enhanced saturation solubility might be due to NP size effects, reduced crystallinity, phytochemical-induced hydrophilicity, and effective drug encapsulation, collectively improving the bioavailability and therapeutic efficacy of AmB at the target site. The AmB release profile showed pH-sensitive, sustained release, with higher rates at infection-site (pH 5.5), ensuring prolonged therapeutic effects. Antifungal tests demonstrated significant zone of inhibition for the conjugate (47 mm) against Candida albicans, outperforming MLE (34 mm), AmB (41 mm) and ZnONPs (37 mm) alone. The conjugate showed 2.4-fold higher LC₅₀ (446.51 μg/mL) over AmB (186.39 μg/mL), suggesting reduced toxicity, likely due to phytochemical capping minimizing non-specific interactions with healthy cells and pH-sensitive, targeted release. Further, the hemolysis study demonstrated that ZnONPs significantly reduced AmB-induced RBC lysis (4.1 % at 24 h vs. 18.1 % for pure AmB), outperforming lipid-based formulations (9–14 %), highlighting their potential as a safer nanocarrier for AmB delivery while mitigating dose-dependent hemolysis. These findings highlight the potential of gZnONPs as an effective nanocarrier for AmB, offering enhanced solubility, targeted antifungal activity, and reduced toxicity, making it a promising alternative to conventional formulations.