Microfluidics‐Assisted Engineering of pH/Enzyme Dual‐Activatable ZIF@Polymer Nanosystem for Co‐Delivery of Proteins and Chemotherapeutics with Enhanced Deep‐Tumor Penetration

The impermeable barriers of solid tumors restrict the co-delivery of protein-based drugs and chemotherapeutics for cancer treatment. Therefore, we developed a ZIF-DOX/RA@DG nanosystem that encapsulates ribonuclease A (RA) and doxorubicin (DOX) in a zeolitic imidazolate framework (ZIF-8) core, with a dextran-based coating (DG). The nanosystem exhibits dual-responsiveness due to γ-glutamyl transpeptidase-activatable cationization and acidic microenvironment-triggered degradation. The DG-coating process was achieved using a microfluidic approach, which stabilized the polymer responsiveness, ZIF-8-based structure, and bioactivity of the encapsulated therapeutics. In vivo results confirmed that the nanosystem could co-deliver RA and DOX to deep impermeable lesions with a synergistic anticancer therapeutic effects. Such a multi-drug delivery system based on an intelligent-responsive design and a microfluidics-assisted synthesis strategy shows great clinical prospects.