Biomacromolecule-MOF Composites for Intracellular Delivery: From Empirical Construction to Rational Design and AI-Assisted Screening.

Biomacromolecules, including proteins, peptides, and nucleic acids, hold great promise for disease diagnosis and therapy because they can execute highly specific biological functions, including catalysis, molecular recognition, and gene regulation. Nevertheless, their clinical translation is limited by inefficient intracellular delivery due to poor membrane permeability, endo/lysosomal entrapment, and instability in complex biological environments. Metal-organic frameworks (MOFs), featuring high porosity, tunable structures, mild encapsulation conditions, versatile surface modification, and stimulus-responsive degradation, have emerged as attractive material platforms for biomacromolecule protection and intracellular delivery. This review summarizes the design evolution of biomacromolecule-MOF composites from empirical construction to rational design and AI-assisted screening. Recent advances in AI-assisted enzyme-MOF and drug-delivery MOF design are further discussed as emerging tools for synergistic integration of multiple functions. This review provides an overview of how MOFs can be developed into next-generation intracellular delivery platforms and how emerging design strategies enable the rapid and precise development of biomacromolecule-MOF composites tailored for specific biomedical applications.