MnO₂-mediated pH-responsive hyaluronated liposomes for singlet oxygen generation in hypoxic tumor environments

In this study, we developed pH-responsive hyaluronated liposomes designed to enable efficient photodynamic therapy in hypoxic tumor environments. First, hyaluronic acid (HA) was chemically conjugated with 3-(diethylamino)propylamine (DEAP, serving as a pH-responsive moiety) and chlorin e6 (Ce6, a photodynamic model drug), resulting in a compound designated as Ce6-HDEA. MnO₂ nanoparticles, serving as oxygen-generating agents through reaction with H₂O₂, were synthesized via an in situ redox reaction by mixing KMnO₄ with bovine serum albumin (BSA). Subsequently, hyaluronated liposomes were prepared with hydrogenated soy phosphatidylcholine (HSPC) and Ce6-HDEA using thin-film hydration, followed by encapsulation of MnO₂ nanoparticles into the liposomes via extrusion, producing a formulation referred to as (MnO₂/Ce6-HDEA)@Lipo. The (MnO₂/Ce6-HDEA)@Lipo liposomes were effectively internalized into MDA-MB-231 tumor cells via HA/CD44 receptor-mediated endocytosis. At an endosomal pH of 6.5, the DEAP moieties in Ce6-HDEA became protonated, destabilizing the liposomal structure and enhancing the release of MnO₂ nanoparticles. These MnO₂ nanoparticles then oxidized H₂O₂, generating oxygen and alleviating hypoxia in the tumor microenvironment. Our findings indicate that upon near-infrared (NIR) laser irradiation, the (MnO₂/Ce6-HDEA)@Lipo substantially increased singlet oxygen production, thereby enhancing photodynamic antitumor efficacy in hypoxic tumor environments.