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Unlike prior reviews centered mainly on individual applications, this review adopts a structure\u2010property\u2010bioperformance\u2010translation framework to clarify how COF design governs biological function and clinical promise. We analyze how linkage chemistry, topology, pore environment, surface properties, and particle engineering influence protein corona formation, biodistribution, degradation, therapeutic efficacy, and safety. Particular attention is given to translational challenges still under\u2010represented in the literature, including synthesis under biomedical constraints, scalability, reproducibility, residual solvent and impurity control, sterilization, green chemistry, and regulatory compatibility. We further discuss the expanding roles of COFs in drug and biomacromolecule delivery, photodynamic, photothermal, and chemodynamic therapy, as well as in emerging immunotherapeutic and combination treatment platforms. 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