Core–Shell Structured Metal–Organic Frameworks for pH-Triggered Combination Photodynamic/Chemotherapy-Based Cancer Treatment

The use of hypoxia-activated prodrugs is a promising strategy to address the limitations of photodynamic therapy (PDT) caused by a hypoxic tumor microenvironment. However, the controlled release of these hypoxia-activated prodrugs during PDT remains a challenge. In this study, we present a metal–organic framework (MOF) with a core–shell structure that can achieve a high PDT efficacy and on-demand release of hypoxia-activated prodrugs (AQ4N) for hypoxic tumor therapy. The nanocomposites were created by assembling zeolitic imidazolate frameworks (ZIF-8) onto the surface of AQ4N-encapsulated porphyrinic MOF, followed by surface functionalization with folic acid-conjugated polyethylene glycol. AQ4N is entrapped in the mesopores of MOFs, and it shows acidic environment-triggered release due to the degradation of the ZIF-8. When exposed to laser, porphyrinic MOFs can produce reactive oxygen species for PDT. At the same time, PDT exacerbates hypoxia at the tumor site, leading to the bioreduction of AQ4N to AQ4 for enhanced anticancer activity. This work presents a practical approach to improve the tumor-targeting and therapeutic efficiency of hypoxic tumors.