The protection of unstable anticancer molecules and their delivery to lesions are challenging issues in cancer treatment. Topotecan (TPT), a classic cytotoxic drug, is widely used for treating refractory lung cancer. However, the therapeutic effects of TPT are jeopardized by its active lactone form that is intrinsically hydrolyzed in physiological fluids, resulting in low bioavailability. Herein, the TPT-loaded crosslinked cyclodextrin metal-organic framework (TPT@CL-MOF) was engineered to improve the local bioavailability of TPT for the treatment of lung cancer. CL-MOF exhibited the efficient loading (12.3 wt%) of TPT with sustained release characteristics. In particular the formulation offered excellent protection in vitro against hydrolysis and increased the half-life of TPT from approximately 0.93 h to 22.05 h, which can be attributed to the host–guest interaction between cyclodextrin and TPT, as confirmed by molecular docking. The TPT@CL-MOF could effectively kill the cancer cells and inhibit the migration and invasion of B16F10 cells in vitro. Moreover, TPT@CL-MOF was efficiently distributed in the lungs after intravenous administration. In an in vivo study using a B16F10 pulmonary metastatic tumor model, TPT@CL-MOF significantly reduced the number and size of metastatic lung nodules at a reduced low dose by five times, and no noticeable side effects were observed. Therefore, this study provides a possible alternative therapy for the treatment of lung cancer with the camptothecin family drugs or other unstable therapeutically significant molecules.

γ-Cyclodextrin metal–organic frameworks (γCDMOF) recently emerged as biofriendly, highly porous, and crystalline materials with potential applications in drug delivery. However, little is known about their drug entrapment and release characteristics, which are key parameters in the design of drug carriers. The macroscopic properties of a material are determined by its microstructure. Thus, the characteristics of the constitutive units of the cubic crystalline γCDMOF determine their drug loading and release behaviors. In this study, the release profile of prednisolone (PNS) form γCDMOF was predicted, and the mechanism was analyzed based on the γCDMOF molecular structure. For the first time, experimental, molecular simulation, and mathematical modeling methods were combined to gain insights into the drug distribution in cubic porous crystals of γCDMOF as well as on drug release kinetics. The predicted release profile was in good agreement with the experimental results, showing that the modeling method was reliable. The methodology developed here could provide a reference for further investigations of drug penetration and release in supramolecular systems.