Autophagy-Regulating, Photothermal Polydopamine-Coated, and Photodynamic Zirconium/Porphyrin-Framed Metal–Organic Frameworks for Enhanced Doxorubicin Therapy in Colon Cancer

Metal-organic frameworks (MOFs) have immense potential for biomedical applications. This paper reports the development of multifunctional zirconium-based metal-organic framework (ZrMOF) nanohybrids, featuring a photodynamic porphyrin-framed zirconium cluster with photothermal polydopamine (PD) coating. The PD-coated ZrMOF (PD/ZrMOF) nanohybrids exhibit enhanced colloidal stability and biocompatibility. The PD/ZrMOF nanohybrids in the present study exhibited a unique combination of functionalities, including photodynamic therapy (PDT), photothermal therapy (PTT), and the delivery of anticancer agents. Furthermore, hydrazone-modified doxorubicin (DOX-hyd) was encapsulated within the PD/ZrMOF nanohybrids, enabling a pH-responsive release mechanism that responds to acidic conditions within the tumor microenvironment. This study examined how MOFs influence autophagy, which is essential for maintaining cellular homeostasis in various human diseases, resulting in autophagy activation by MOF treatment. Additional research into the possible mechanisms of autophagy by MOF showed that the up-regulation of Beclin-1 and ATG7, independent of the mTOR pathway, contributes to autophagy induction. Furthermore, the DOX-hyd-encapsulated PD/ZrMOF nanohybrids (DOX-hyd-PD/ZrMOF) exhibited remarkable cancer suppression ability in vitro and in vivo, owing to their tri-mode therapeutic capabilities comprising PDT, PTT, and chemotherapy. This versatile "three-in-one" nanoplatform enables efficient cancer imaging and offers a powerful strategy for multi-mode combination treatments.