Adapting and Remolding: Orchestrating Tumor Microenvironment Normalization with Photodynamic Therapy by Size Transformable Nanoframeworks

Abnormal tumor microenvironment (TME) not only facilitates tumor proliferation and metastasis, but also establishes physiological barriers for effective transport of therapeutics inside the tumor, posing great challenges for cancer treatment. Here we designed a core-satellite size transformable nanoframework (denoted as T-PFRT) that can synchronously adapt to and remold TME for augmenting photodynamic therapy to inhibit tumor growth and prevent tumor metastasis. Upon matrix metalloproteinase 2 (MMP2)-responsive dissociation of the nanoframework in TME, the core structure loaded with TGFβ signaling pathway inhibitor and oxygen-carrying hemoglobin aims to stroma remodeling and hypoxia relief, allowing the photosensitizer-encapsulated satellite particles to penetrate to deep-seated tumor for oxygen-fueled photodynamic therapy. We demonstrated that T-PFRT could overcome the stroma and hypoxia barriers for delivering therapeutics, and gain excellent therapeutic outcomes in the treatment of primary and metastatic tumors.