Covalent organic frameworks (COFs) are crystalline and porous materials formed from periodically organized organic molecules bonded covalently to create highly stable architectures. Their mechanical properties can be precisely adjusted through structural modifications, making COFs exceptionally suitable for applications in cancer treatment and drug delivery. This review summarizes strategies for controlling the mechanical properties of COFs, including adjustments in structural dimensions, pore sizes and host-guest interactions. The remarkable advancements in drug delivery, cancer therapy, photodynamic therapy and photothermal therapy achieved through COFs with tunable mechanical properties are then discussed. By providing deeper insights into the biomedical applications of COF systems, this review aims to foster interdisciplinary research combining nanomedicine and COF materials. Additionally, the review explores recent studies and discoveries on COFs' potential as innovative drug carriers capable of biological overcoming barriers such as the blood-brain barrier, nasal mucosa, cutaneous layers and oral mucosa. Greater insight into both the limitations and potential of COFs could pave the way for developing more effective and targeted strategies within this challenging field. (c) 2025 Published by Elsevier B.V. on behalf of Shenyang Pharmaceutical University. ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )