Bioorthogonal-based prodrug activation strategy holds great potential in reducing the severe side effects of chemotherapy and has been widely applied in the development of in situ personalized cancer vaccines. However, current strategies mainly focus on the caging and release of cytotoxic drugs, while the simultaneous enhancement of drug accumulation and penetration within tumors remains underexplored. Here, we modularly design a tetrazine (Tz)-modified peptide (TMP) capable of cascade responsiveness to the tumor microenvironment and biomarkers, leading to the in situ self-assembly of an artificial topological nanostructure (ATNs) catalytic system on the tumor cell surface. This system significantly increases the local concentration of bioorthogonal handles (Tz), thereby improving the activation efficiency of the prodrugs trans-cyclooctene (TCO)-doxorubicin (Dox) and TCO-imiquimod (IMQ). We demonstrated that activated Dox induced immunogenic cell death (ICD) by releasing tumor-associated antigens (TAAs), while activated IMQ further amplified immune stimulation, leading to tumor ablation. Additionally, ATNs inhibit tumor cell migration, regulate tumor tissue permeability, and ultimately promote the penetration of the activated drugs. In vivo results demonstrated that the ATNs catalytic system enhanced drug penetration by 7.8-fold in tumor tissues and exhibited excellent safety and selectivity, leading to markedly improved survival outcomes. Moreover, this system also showed promising therapeutic effects in preventing tumor recurrence. We postulate that the synergistic integration of in situ self-assembly and bioorthogonal catalysis offers great potential for the safe and effective development of in situ cancer vaccines and holds promise as a universal prodrug delivery platform for cancer therapy.
Dong et al. (Sun,) studied this question.