Metallized hollow-COF nanobowls with dual-mode ROS generation for cancer sonodynamic therapy†

Sonodynamic therapy (SDT) has emerged as an encouraging route in tumor treatment, due to its exceptional tissue penetration depth and favorable safety profile. Nevertheless, the clinical translation of conventional organic sonosensitizers is hindered by intrinsic limitations, including pronounced hydrophobicity, insufficient chemical stability, and low reactive oxygen species (ROS) production. In contrast, hollow covalent organic frameworks (HCOFs) exhibit exceptional cargo-loading capabilities, structural robustness, and biocompatibility, positioning them as ideal nanoplatforms for advanced therapeutic applications. Herein, we engineered a bowl-shaped HCOF architecture designed to amplify ultrasonic cavitation effects. This nanostructure was subsequently functionalized with the sonosensitizer (Hemin) and subjected to strategic metallization via metal ion incorporation, culminating in the development of a high-efficiency antitumor nanosystem (FeHHCA). FeHHCA can achieve dual-mode ROS generation, namely, sonodynamic synergistically generating ¹O₂ and being specifically activated by a tumor microenvironment (TME) to generate ˙OH through a Fenton-like reaction, achieving an 78.7% tumor inhibition rate in vivo. These findings offer innovative approaches and strategies for the design of hollow COFs and offer great potential for the application of SDT in cancer treatment.