Introduction: Cryptococcus (C.) neoformans is a pathogen capable of breaching the blood–brain barrier (BBB) and localising in the brain, presenting challenges for treatment. This is, in part, because amphotericin B cannot cross the BBB, and while fluconazole can cross the BBB, its use is limited by non-fluconazole susceptibility. This study aimed to reformulate aspirin by encapsulating it into D-α-tocopheryl polyethylene glycol succinate (TPGS), to characterise the formulation, and to evaluate its in vitro efficacy against C. neoformans.

Methods: Aspirin was encapsulated into TPGS using a colloidal dispersion method. The aspirin–TPGS micelles were characterised using Fourier transform infrared spectroscopy (FTIR) and a Zeta particle analyser. The EUCAST protocol was used to assess the cryptococcal growth susceptibility to aspirin–TPGS at 0, 1, 2, and 4 mM concentrations. For a comparative analysis, cells were also treated with standard aspirin, TPGS, fluconazole, and amphotericin B at the same concentrations.

Results: The FTIR spectra analysis confirmed the successful encapsulation of aspirin into TPGS. The aspirin–TPGS nanoparticles were 10.97 nm in size with a polydispersity index of 0.175 and a zeta potential of 3.668. Aspirin in TPGS was found to be more potent than standard aspirin powder at 1, 2, and 4 mM, which may have been due to increased lipophilicity that facilitated cellular entry. The aspirin–TPGS formulation was more effective than fluconazole at 1, 2, and 4 mM based on the calculated p values and showed a similar efficacy to that of amphotericin B. The results showed that aspirin–TPGS significantly reduced the cryptococcal growth after 48 hours compared to that in the untreated controls.

Conclusion: These findings indicate that aspirin–TPGS micelles exhibit a potent inhibitory effect on C. neoformans, offering potential as a treatment for cryptococcal infections. Further studies will investigate aspirin–TPGS’s ability to traverse the BBB using an in vitro model of hCMEC/D3 cells, enhancing our understanding of its therapeutic potential in complex biological systems.