Aqueous-phase synthesis of upconversion metal-organic frameworks for ATP-responsive in situ imaging and targeted combinational cancer therapy

Herein, the nanoscaled ATP-responsive upconversion metal-organic frameworks (UCMOFs) are aqueous-phase synthesized for co-delivery of therapeutic protein cytochrome c (Cyt c) and chemodrugs doxorubicin (DOX), achieving targeted combinational therapy of human cervical cancer. The UCMOFs are rationally fabricated by growing ZIF-90 on mesoporous silica-coated upconversion nanoparticles (UCNPs), in which the ZIF-90 layer attenuates the upconversion luminescence (UCL) and the rigid frameworks increase the stability of encapsulated proteins. Once the UCMOF@DOX/Cyt c are internalized into HeLa cells via specific recognition of sgc8 aptamers, the intracellular ATP triggers the dissolution of ZIF-90 into Zn2+, which facilitates not only the release of Cyt c and DOX but also the restoration of UCL for real-time monitoring of drug release. It has been demonstrated that the therapeutic efficacy is greatly improved by the combination of caspase-mediated apoptosis activated by Cyt c (protein therapeutics), DNA fragmentation induced by DOX (chemotherapy), and Zn2+-promoted generation of reactive oxygen species (ROS) (oxidative stress). Overall, our proposed multifunctional UCMOFs provide an effective platform for targeted combinational cancer therapy and in situ imaging, which hold great promise in biomedical and clinical applications.