From Morphology to Therapy: A Translation-Focused Review of Covalent Organic Frameworks for in Vivo Applications.

Since their pioneering synthesis in 2005, covalent organic frameworks (COFs) have achieved rapid progress in synthetic methodologies and structural precision. These materials exhibit high specific surface areas and well-ordered porous architectures, endowing them with broad application prospects in areas such as gas adsorption, catalysis, energy storage, and biomedicine. Particularly in the biomedical field, since their proposal as drug carriers in 2015, COFs have attracted growing interest owing to their high drug-loading capacity and facile functionalization. Following the first reported in vivo study in 2018, COFs have been successfully utilized for encapsulating therapeutic agents. Through the incorporation of stimuli-responsive systems-such as pH sensitivity and hypoxia responsiveness-they have been engineered into targeted therapeutic platforms for diseases including cancer. Nonetheless, substantial challenges remain for their clinical translation. To this end, this review systematically summarizes the morphological classifications of COFs and representative in vivo studies, while addressing key obstacles including scalable synthesis, long-term toxicity evaluation, and AI-guided design. It aims to provide insightful perspectives and guidance for the development and clinical translation of next-generation COF-based biomaterials.