Covalent Organic Framework (COFs) in Targeted Drug Delivery and Therapeutics: A Critical Review

Covalent organic frameworks (COFs) are an emerging type of crystalline, porous polymers which are formed through covalent bonds using designed organic building blocks. Their high pore structuring, high surface area, and modular chemistry make them attractive platforms for targeted drug delivery and multimodal therapeutics. This is a critical review of the developments in the field of foundational COF chemistry to the most recent biomedical applications, especially with regard to drug encapsulation mechanisms (physical adsorption, covalent conjugation, and host-guest interactions), stimulus-responsive release strategies (pH, redox, enzyme, light), and targeting of the host (passive EPR accumulation and active ligand directed delivery). It focuses on discussion around nanoscale COF fabrication and functionalization approaches that permit controlled loading, colloidal stability, and receptor-mediated uptake, and multifunctional and theranostic COF systems that combine photodynamic/photothermal therapy, catalytic nanozyme activity, gene delivery, and multimodal imaging. In the literature, COFs have shown excellent drug loading capabilities and preclinical efficacy potentials. However, translation is a bottleneck due to several factors, including reproducibility, hydrolytic stability of linkages, full pharmacokinetics/toxicology, and scalable GMO-compatible synthesis. It reported methodological heterogeneities with loading/release assays and advocates standardized reporting (DLC, EE, release conditions, pre-/and post-structural characterization) and intensive in vivo PK/PD and immunotoxicity investigations. Lastly, strategic priorities were outlined in the field, which include rational linkage selection of biodegradability, orthogonal post-synthetic modification protocols, integration of computational design tools, and specific translational work to fast-track clinical translation of COF-based nanomedicines. Taken together, this review evaluates the potential and practical challenges of the COFs as next-generation targeted delivery and therapeutic vehicles.