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

Abstract 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.