Bioorthogonal chemistry provides a new avenue for disease treatment by generating therapeutic agents in situ. However, two crucial issues have to be considered for future practical applications. One is the prevention of metabolic inactivation of the in situ-synthesized drug molecules. The other is enhancing the biocompatibility and tumour cell selectivity of the bioorthogonal catalyst. Here, to tackle the above issues, we design a biocompatible hydrogen-bonded organic framework-based dual prodrugs activation platform (namely Apt@E-F@PHOF-1). The ferric porphyrin ligands of hydrogen-bonded organic framework-based bioorthogonal pre-catalyst are reduced to ferrous porphyrin by the abundant glutathione in tumour, which then catalyses the cleavage reaction to synthesize 5-fluorouracil (5FU) and 5-ethynyluracil. The 5FU catabolic enzyme inhibitor 5-ethynyluracil prevents 5FU metabolic inactivation. As an example of hydrogen-bonded organic framework-based bioorthogonal prodrug activation, this work provides insights into prevention of drug inactivation by using bioorthogonal chemistry, thus enhancing tumour inhibition and reducing therapeutic side effects demonstrated by both in vitro and orthotopic metastatic mouse model experiments.
