Metalloporphyrin MOFs‐Based Nanoagent Enabling Tumor Microenvironment Responsive Sonodynamic Therapy of Intracranial Glioma Signaled by NIR‐IIb Luminescence Imaging

Abstract Noninvasive sonodynamic therapy (SDT) shows promise for brain glioma treatment due to deep tissue‐penetrating capabilities (>10 cm) of ultrasound and high spatial resolutions. Yet, this technique is hindered by inefficient production of reactive oxygen species (ROS), resulting from the hypoxic tumor microenvironment (TME), high level of ROS scavenger glutathione (GSH), and the inability to visualize glioma in vivo for precise treatment management and monitoring in current sonosentizers. To address these challenges, we fabricated a core‐shell heterostructure sonosensitizer (labeled as DFM), in which meso‐tetra (4‐carboxyphenyl) porphine (TCPP) porphyrin metal‐organic frameworks (MOF, PCN‐224(Fe)) serve as a porous shell to contain approved chemotherapeutics sorafenib (SRF) to effectively inhibit GSH synthesis, while NaErF 4 :Yb@NaLuF 4 nanoparticles as the core provide TME‐responsive NIR IIb (≈1500–1800 nm) luminescence at 1525 for precise optical imaging. Coordination of Fe 3+ into the macrocycle of TCPP at the MOFs shell is found to, besides triggering ferroptosis, reduce TCPP phosphorescence (23% decrease) and increase the triplet state ( T 1 ) oxygen quenching, substantially promoting the singlet oxygen generation (2.6‐fold increase). Furthermore, GSH in TME facilitates the reduction of Fe 3+ to Fe 2+ , thereby eliminating the luminescence quenching of Fe 3+ and augmenting the NIR IIb luminescence of Er 3+ (5‐fold increase) for nanoagents accumulation imaging in intracranial glioma, realizing dynamical monitoring of SDT processes. Compared to control groups, in vitro and in vivo experiments confirm the effective ROS generation and results in a 6‐fold volume reduction of brain gliomas, reaching a survival rate of 80% at 30 days posttreatment.