An Oxygen Self-Sufficient Nanozyme Engineered From Metal-Organic Cage for Dual-Modal Self-Reporting Theranostics

The development of intelligent theranostic platforms capable of improving tumor-hypoxic microenvironment and self-reporting therapeutic status is crucial for overcoming the limitations of conventional photodynamic therapy (PDT). Herein, we report an oxygen self-sufficient nanozyme by the functionalization of manganese dioxide (MnO₂) nanoflowers with supramolecular metal-organic cage (MOC52-L) photosensitizers for dual-modal self-reporting theranostics. This nanozyme integrates catalase-mimetic activity for oxygen generation with therapeutic enzyme activities, enabling enhanced type I/II combined PDT. The decomposition of MnO₂ component in tumor microenvironment not only efficiently generates oxygen and activates PDT but also specifically triggers the recovery of fluorescence and T1-weighted magnetic resonance imaging (MRI) signals. The activation of these signals provides real-time visualization of tumor accumulation and serves as a direct reporter of successful hypoxia alleviation and therapeutic initiation. Moreover, the pockets of MOC52-L can be employed to capture low-water-soluble lificiguat (YC-1) as effective inhibitors of HIF-1α for further anti-angiogenesis and anti-metastasis. Both in vitro and in vivo studies demonstrated that this nanozyme can non-invasively visualize the effective treatment zone via signal turn-on and achieve excellent anti-tumor performance with high biosafety. This work establishes a generalizable strategy for designing silenced theranostics agents, enabling a single activatable core to enhance imaging-guided PDT and trigger turn-on self-reporting.