Dual “Unlocking” Strategy to Overcome Inefficient Nanomedicine Delivery and Tumor Hypoxia for Enhanced Photodynamic‐Immunotherapy

Abstract Lacking blood vessels is one of the main characteristics of most solid tumors due to their rapid and unrestricted growth, which thus causes the inefficient delivery efficiency of nanomedicine and tumor hypoxia. Herein, a dual “unlocking” strategy to overcome these obstacles is proposed by combining engineered hybrid nanoparticles (named ZnPc@FOM‐Pt) with dexamethasone (DXM). It is verified that pretreatment of tumors with DXM can increase intratumorally micro‐vessel density (delivery “unlocking”) to enhance the tumor delivery efficiency of ZnPc@FOM‐Pt and decrease HIF‐1α expression. Correspondingly, more Pt can catalyze tumor‐overexpressed H2O2 to produce oxygen to further cause hypoxia “unlocking,” ultimately achieving boosted ZnPc‐based photodynamic therapy in vivo (tumor inhibition rate: 99.1%). Moreover, the immunosuppressive tumor microenvironment is efficiently reversed and the therapeutic effect of anti‐PD‐L1‐based immunotherapy is promoted by this newly designed nanomedicine. This dual “unlocking” strategy provides an innovative paradigm on simultaneously enhancing nanomedicine delivery efficacy and hypoxia relief for tumor therapy.