Hierarchical Self‐assembly of Discrete Metal–Organic Cages into Supramolecular Nanoparticles for Intracellular Protein Delivery

Hierarchical self‐assembly (HAS) is a powerful approach to create supramolecular nanostructures for biomedical applications. This potency, however, is generally challenged by the difficulty of controlling the HAS of biomacromolecules and the functionality of resulted HAS nanostructures. Herein, we report a modular approach for controlling the HAS of discrete metal–organic cages (MOC) into supramolecular nanoparticles, and its potential for intracellular protein delivery and cell‐fate specification. The hierarchical coordination‐driven self‐assembly of adamantane‐functionalized M12L24 MOC (Ada‐MOC) and the host–guest interaction of Ada‐MOC with β‐cyclodextrin‐conjugated polyethylenimine (PEI‐βCD) afford supramolecular nanoparticles in a controllable manner. HAS maintains high efficiency and orthogonality in the presence of protein, enabling the encapsulation of protein into the nanoparticles for intracellular protein delivery for therapeutic application and CRISPR/Cas9 genome editing. Self‐assembly of Ada‐MOC and host–guest interaction with β‐cyclodextrin‐conjugated polyethylenimine (PEI‐βCD) affords supramolecular nanoparticles. Hierarchical self‐assembly of Ada‐MOC and PEI‐βCD maintains high efficiency and orthogonality in the presence of protein, enabling protein encapsulation into nanoparticles for intracellular protein delivery for therapeutic application and CRISPR/Cas9 genome editing.