Unlocking the Unreachable: Cationic ThermoSomes for Next-Generation Posaconazole Therapy.

Invasive fungal infections (IFIs) represent a serious global health threat due to rising incidences and drug resistance. Traditional antifungal therapies face limitations, including toxicity, rapid clearance, and resistance, demanding nanotechnology-driven solutions. While lipid-based formulations, such as AmBisome, have achieved clinical success, scalability is restricted by high costs and complex manufacturing. This study advances the solvent-free approach by developing "ThermoSomes", bilayered lipid vesicles encapsulating the FDA-approved antifungal Posaconazole (PCZ) for IFI treatment. The formulation was optimized through in silico drug-excipient interaction studies, validated in vitro, and optimized using Quality-by-Design (QbD). A 6-fold improvement was observed in fungal cell internalization of cationic ThermoSomes compared to anionic and neutral counterparts, owing to ionic interactions with the fungal cell wall. Pharmacokinetic studies showed improvements in parameters like AUC0-48 h by 4.68-fold and t1/2 by 1.37-fold. In vivo studies demonstrated that intravenous PCZ-ThermoSomes outperformed the conventional marketed solution (Noxafil) in terms of therapeutic efficacy, exhibiting approximately 2-fold greater reduction in fungal burden across all critical organs in a murine candidiasis model. Here, we have broadened the therapeutic framework of PCZ by targeting critical organs and maintaining therapeutic concentrations, which are difficult to achieve by conventional formulations. Thus, PCZ-ThermoSomes serve as a safe, stable, nontoxic, efficacious, scalable, and cost-effective alternative to existing treatment modalities for IFIs.