Rationally Designed Thiazole-Based COF with Multiphoton Activity for Drug Delivery and Synergistic Therapy of Deep-Seated Tumors

Multiphoton photosensitizers activated by near-infrared light have attracted considerable attention in the fields of homogeneous photocatalysis, optical imaging, and phototherapy because of their negligible interference, low dilapidation, and deep penetration. Nonetheless, most multiphoton photosensitizers still face issues such as poor long-range ordering, strong π-π stacking hindrances, and potential metal toxicity. In this study, a rationally designed thiazole-based covalent organic framework (DT-COF) with multiphoton activity was efficiently harvested via one-step preparation from inactive small molecules—namely, dithiooxamide and 1,3,5-triformylbenzene. Theoretical calculation and characterization tests revealed that the good performances of deeper multiphoton fluorescence and photodynamic therapy benefited from the donor-π-acceptor configuration, highly ordered long-range structure, weakened π-π stacking interaction between the layers, and good nonlinear optical properties. Furthermore, tirapazamine (TPZ), a hypoxia-activated chemotherapeutic drug, was encapsulated into DT-COF pores with anastomosing dimensions (encapsulation efficiency = 75%). The DT-COF targeted the mitochondria and delivered TPZ to the nucleus. Additionally, the DT-COF consumed oxygen to generate ¹ O ₂ , promoting TPZ activation and realizing a combination of photodynamic and chemotherapeutic anti-tumor therapy. This study provides a new strategy for the development of multiphoton photosensitizers and demonstrates their potential in cancer theranostics.