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. A novel pH/enzyme dual‐activatable nanoplatform (ZIF@DG) was developed via in situ encapsulation of therapeutics into a zeolitic imidazolate framework ZIF‐8, combined with microfluidics‐assisted preparation of a DG polymer coating. The nanoplatform can co‐deliver the protein drug ribonuclease A and the small‐molecule drug doxorubicin with controlled drug release to deep tumor regions for synergistic cancer therapy.