Reactive Oxygen Species–Activatable Liposomes Regulating Hypoxic Tumor Microenvironment for Synergistic Photo/Chemodynamic Therapies

Tumors have adapted various cellular antidotes and microenvironmental conditions to subsist against photodynamic therapy (PDT) and chemodynamic therapy (CDT). Here, the development of reactive oxygen species (ROS)‐activatable liposomes (RALP) for therapeutic enhancement by simultaneously addressing the critical questions in PDT and CDT is reported. The design of RALP@HOC@Fe₃O₄ features ROS‐cleavable linker molecules for improved tumor penetration/uptake and ondemand cargo releasing, and integration of Fe₃O₄ and an oxaliplatin prodrug for smart regulation of hypoxia tumor microenvironment. Glutathione stored by the tumor cells is consumed by the prodrug to produce highly toxic oxaliplatin. Depletion of glutathione not only avoids the undesired annihilation of ROS in PDT, but also modulates the chemical specie equilibria in tumors for H₂O₂ promotion, leading to greatly relieved tumor hypoxia and PDT enhancement. Synergistically, Fe (II) in the hybrid RALP formulation can be fuelled by H₂O₂ to generate ?OH in the Fenton reaction, thus elevating CDT efficiency. This work offers a strategy for harnessing smart, responsive, and biocompatible liposomes to enhance PDT and CDT by regulating tumor microenvironment, highlighting a potential clinical translation beneficial to patients with cancer.