Insights into the Biological Activity and Bio‐Interaction Properties of Nanoscale Imine‐Based 2D and 3D Covalent Organic Frameworks

Abstract Covalent Organic Frameworks (COFs) emerged as versatile materials with promising potential in biomedicine. Their customizable functionalities and tunable pore structures make them valuable for various biomedical applications such as biosensing, bioimaging, antimicrobial activity, and targeted drug delivery. Despite efforts made to create nanoscale COFs (nCOFs) to enhance their interaction with biological systems, a comprehensive understanding of their inherent biological activities remains a significant challenge. In this study, a thorough investigation is conducted into the biocompatibility and anti‐neoplastic properties of two distinct imine‐based nCOFs. The approach involved an in‐depth analysis of these nCOFs through in vitro experiments with various cell types and in vivo assessments using murine models. These findings revealed significant cytotoxic effects on tumor cells. Moreover, the activation of multiple cellular death pathways, including apoptosis, necroptosis, and ferroptosis is determined, supported by evidence at the molecular level. In vivo evaluations exhibited marked inhibition of tumor growth, associated with the elevated spontaneous accumulation of nCOFs in tumor tissues and the modulation of cell death‐related protein expression. The research contributes to developing a roadmap for the characterization of the intricate interactions between nCOFs and biological systems and opens new avenues for exploiting their therapeutic potential in advanced biomedical applications.