Tailored Covalent Organic Framework Platform: From Multistimuli, Targeted Dual Drug Delivery by Architecturally Engineering to Enhance Photothermal Tumor Therapy.

Engineering bulk covalent organic frameworks (COFs) to access specific morphological structures holds paramount significance in boosting their functions in cancer treatment; nevertheless, scant effort has been dedicated to exploring this realm. Herein, silica core-shell templates and multifunctional COF-based reticulated hollow nanospheres (HCOFs) are novelly designed as a versatile nanoplatform to investigate the simultaneous effect of dual-drug chemotherapy and photothermal ablation. Taking advantage of the distinct structural properties of the template, the resulting two-dimensional (2D) HCOF, featuring large internal voids and a peripheral interconnected mesoporous shell, presents intriguing benefits over its bulk counterparts for cancer treatment, including a well-defined morphology, an outstanding drug loading capability (99.6%) attributed to its ultrahigh surface area (2087 m 2 /g), great crystallinity, improved tumor accumulation, and an adjustable drug release profile. After being loaded with hydrophilic doxorubicin with a remarkable loading capacity, the obtained drug-loaded HCOFs were coated with gold nanoparticles (Au NPs) to confer them with three properties, including pore entrance blockage, active-targeting capability, and improved biocompatibility via secondary modification, besides high near infrared (NIR) absorption for efficient photothermal hyperthermia cancer suppression. The resultant structure was functionalized with mono-6-thio-β-cyclodextrin (β-CD) as a second pocket to load docetaxel as the hydrophobic anticancer agent (combination index = 0.33). The dual-drug-loaded HCOF displayed both pH- and near-infrared-responsive on-demand drug release. In vitro and in vivo evaluations unveiled the prominent synergistic performance of coloaded HCOF in cancer elimination upon NIR light irradiation. This work opens up a new avenue for exciting applications of structurally engineered HCOFs as hydrophobic/hydrophilic drug carriers as well as multimodal treatment agents.