Transfersome enhances nail penetration of antifungal drug and photosensitizer for chemo-photodynamic therapy of onychomycosis in a novel rat model

Onychomycosis is a prevalent nail infection caused by fungi, presenting significant treatment challenges due to poor drug penetration and high recurrence rates. Current treatments, including oral and topical antifungals, often have limited efficacy and can lead to resistance. Transfersomes are lipid vesicles that can penetrate skin for transdermal drug delivery. Here, a t ransfersome (termed THT) capable of penetrating nails to deliver a photosensitizer ( h ematoporphyrin monomethyl ether, HMME) and an antifungal chemotherapeutic drug ( t avaborole) has been developed, achieving a chemo-photodynamic synergistic treatment of onychomycosis. The optimized THT was prepared using a combination of soy lecithin, sodium deoxycholate, and cholesterol in an 8: 4: 0.5 ratio, with a particle size of 200 nm and a 30 % alcohol-water solvent system. This formulation significantly enhanced nail penetration, with the concentration of HMME reaching 330 times higher than that in phosphate-buffered saline. Moreover, THT showed potent fungicidal activity, reducing the survival of Trichophyton rubrum microconidia to as low as 3.24 % under light irradiation, and achieving approximately 90 % treatment efficacy in the ex vivo model. In addition to in vitro and ex vivo verification, an innovative rat onychomycosis model was established to confirm its superior therapeutic efficacy in vivo , with cure rates around 90 % and a significant reduction in fungal hyphae and spores. It is accumulated around and deformed to enter the physiological pores of the nail plate, effectively penetrating to deeper layers at the nail bed. THT, with its high nail penetration efficiency and potent synergistic antifungal activity, represents a promising topical treatment for onychomycosis.