High-loading hexosomes unlock zinc(II) Phthalocyanine for photodynamic therapy

Photodynamic therapy (PDT) is a promising strategy for treating early-stage tumors, relying on light-activated photosensitizers to generate cytotoxic reactive oxygen species. Zinc(II) phthalocyanines are highly effective PDT agents due to their strong red/near-infrared absorption and high singlet oxygen yields. However, poor water solubility and aggregation in aqueous media cause quenching, severely limiting their clinical efficacy. To address this, zinc(II) 2,9,16,23-tetra(amino)phthalocyanine (TAZnPc) was encapsulated into inverse hexagonal liquid crystalline nanoparticles (hexosomes) via solvent-assisted homogenization. This approach increased TAZnPc loading 140-fold compared to direct sonication, achieving highly loaded hexosomes (monoolein: TAZnPc ratio = 33 mol/mol). SAXS and cryo-TEM confirmed the retention of the internal inverse hexagonal (H_II) phase. Biologically, TAZnPc-loaded hexosomes exhibited negligible dark toxicity but marked, light-induced phototoxicity in Calu-3 lung adenocarcinoma cells upon irradiation at 650 nm. Overall, hexosome encapsulation significantly enhanced TAZnPc solubility and delivery without compromising its therapeutic photosensitizing activity, offering a robust nanomedicine platform for improved PDT.