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A Protein@Inorganic Nano-Dumpling System for High-Loading Protein Delivery with Activatable Fluorescence and Magnetic Resonance Bimodal Imaging Capabilities.

The efficient protein delivery into the target cell is highly desirable for protein therapeutics. Current approaches for protein delivery commonly suffer from low-loading protein capacity, poor specificity for target cells, and invisible protein release. Herein we report a protein@inorganic nano-dumpling (ND) system as an intracellular protein delivery platform. Similar to traditional Chinese food, dumpling, ND consists of a protein complex "filling" formed by metal-ion-directed self-assembly of protein cargos fused to histidine-rich green fluorescent proteins (H39GFP), which are further encapsulated by an external surface "wrapper" of manganese dioxide (MnO2) via in situ biomineralization. This ND structure allows for a high loading capacity (> 63 wt.%) for protein cargos with enhanced stability. NDs can be targeted and internalized into cancer cells specifically through folic acid receptors by surface-tailored folic acid. The protein cargo release is in a bistimuli-responsive manner, triggered by either reductive or acidic intracellular microenvironment. Moreover, the MnO2 nano-wrapper is an efficient fluorescence quencher for inner fused GFPs and also a "switch-on" magnetic resonance imaging (MRI) agent via triggered-release of Mn2+ ions, which enables activatable fluorescence/MRI bimodal imaging of protein release. Finally, the ND is highly potent and specific to deliver functional protein ribonuclease A (RNase A) into cultured target cells and tumor site in a xenografted mouse model, eliminating the tumor cells with high therapeutic efficacy. Our approach provides a promising alternative to advance protein-based cancer therapeutics.