Biological Membrane-Inspired Covalent Organic Frameworks for Biointegration and Structure–Function Design

High Resolution Image Download MS PowerPoint Slide Conspectus Biological membranes constitute the fundamental scaffolding of life, serving as sophisticated interfaces that drive cellular function through the spatial compartmentalization of functional units. They integrate enzymatic catalysis, molecular recognition, and regulated transport within finely tuned microenvironments, ensuring exceptional efficiency, selectivity, and resilience in biological conversion networks. Translating these advantages beyond native biological contexts remains a central objective in chemical manufacturing, biotechnology, and biomedicine. However, the inherent fragility of enzymes and living cells outside physiological environments, combined with the mismatch between the survival-oriented nature of biological systems and the performance-driven requirements of industrial manufacturing, hinders their broader application. Therefore, bridging the biological sophistication with industrial rigor necessitates the development of programmable synthetic platforms capable of re-encoding these membrane-inspired principles into robust and functional material architectures. Covalent organic frameworks (COFs), featuring long-range-ordered structures, finely tunable nanochannels, high porosity, and chemically tailorable frameworks, offer a compelling platform to address this challenge. Their molecular-level programmability enables precise control over pore sizes and interfacial chemistry, allowing for the construction of confined microenvironments commensurate with biomacromolecules. Beyond serving as immobilization supports, the structural precision of COFs enables function-driven biomimetic engineering. Deeper investigations into biointegration strategies and membrane-mimetic design within COFs are essential for advancing next-generation catalytic, energy, and biomedical materials. In this Account, we summarize our group’s efforts to bridge biological function with COF design along two complementary directions. First, we develop COF-based biointegrated confined microreactors that engineer membrane-inspired catalytic environments for enzymes and living cells. By tailoring confinement dimensions, engineering hydration-like microenvironments, and modulating covalent anchoring interactions, COFs create protective yet tunable nanoscale compartments that stabilize biomacromolecules and optimize their conformations. The assembly of selective transport channels at biointerfaces further enables efficient substrate exchange while excluding detrimental species, extending biocatalysis into harsh or non-native environments. Importantly, these confined architectures further support functional expansion toward continuous-flow operation, multienzyme, and chemoenzymatic cascade systems, transforming isolated biological components into versatile, integrated catalytic platforms. Second, moving beyond biointegration, we demonstrate that COFs can be designed to emulate core structural and functional attributes of biological membranes. Through hydrophilicity-gradient nanochannels, adaptive linkage chemistries, and spatially defined binding pockets, COFs can encode directional transport, hydration regulation, and selective molecular recognition directly into crystalline porous frameworks. Finally, we discuss current challenges and outline future opportunities toward intelligent, adaptive biomimetic architectures. It is expected that this Account would provide an understanding of structure–function relationships in membrane-inspired COF engineering and inspire the development of next-generation biointerfaces for catalysis, energy conversion, environmental remediation, and biomedical technologies.