Targeted Bioorthogonal Chemistry Synergized with p53 Regulation for Enhanced Chemotherapy

Post-translational modifications (PTMs) function as an important mechanism that defines the structural and functional plasticity of proteins, and thus, the regulation of PTMs holds the promise for drug development and disease therapy. p53 is being considered as one of the most important tumor suppressors; however, the lactylation of p53 undermines its anticancer efficacy during chemotherapy. Besides, the off-target toxicity of drugs also limits the effectiveness of p53 activation and tumor inhibition. In light of these, we propose a targeted hydrogen-bonded organic framework (HOF)-based bioorthogonal platform (HA@Pro@HFe) synergized with the regulation of p53 lactylation for enhanced chemotherapy. The platform could selectively activate a prodrug in the tumor microenvironment, catalyzing the generation of doxorubicin (Dox), which not only killed tumor cells directly but also stimulated the activation of p53. In addition, β-alanine avoided the lactylation of p53 and maintained its tumor suppressive function. This work presents a good example for the combination of bioorthogonal chemistry and PTMs regulation, opening a new avenue for the design of effective and safe p53-based cancer treatment.