Physiologically Stable, Epitope-Imprinted, and Double-Gated Metal–Organic Framework Drug Delivery System for Tumor-Targeted Combination Therapy

Nanoscale metal-organic frameworks (MOFs) have shown great potential as drug delivery systems in biomedical applications; however, the poor physiological stability of MOFs in phosphate-based media limits their practical biomedical applications. Moreover, active-targeted delivery systems provide a more effective solution for developing precise personalized therapy regimes. We created a physiologically stable, epitope-imprinted, and double-gated PCN-224(Zr^IV) drug delivery system for tumor-targeted combination therapy of photodynamic therapy (PDT) and two-drug chemotherapy. PCN-224 was functionalized with diaminotriacetate-derived silanes, followed by loading of drug I, and then DNA was bound through Fe³⁺ bridging coordination. DNA not only acted on a gatekeeper (nanogate I) but also served as a nanocarrier for the loading of drug II through intercalation. Epitope-imprinted ZIF-8 films (nanogate II) were subsequently assembled on site, which resisted phosphates in human plasma, protected DNA from nuclease degradation, and achieved selective recognition ability for target receptors on cancer cells. The double gating of DNA and imprinted ZIF-8 films minimized premature drug leakage to enhance targeted delivery and achieved logic-gated drug release for precise tumor chemotherapy. The created double-gated MOF drug system had good physiological stability, actively targeted to cancer cells, and achieved the tumor-targeted combination therapy of PDT and two-drug chemotherapy, which has broad application prospects in cancer gene therapy and the prevention and control of nucleic acid vaccine epidemics.