An Energy-Sustainable and Oxidative-Tolerant Nanofactory of Therapeutic Proteins for Long-Acting Therapy of Inflammatory Bowel Disease

Abstract

The ability to continuously generate bioactive therapeutics at the diseased site is an appealing and crucial advantage for the treatment of chronic relapsing diseases such as inflammatory bowel disease (IBD). Current in situ therapeutic factory strategies mainly rely on plasmid drugs, which are usually associated with poor stability and susceptibility to oxidative degradation in the inflammatory microenvironment. Furthermore, the transcription of plasmid-based drugs to produce therapeutic proteins is an energy-intensive process, whose energy demands are difficult to satisfy at inflammatory sites owing to the compromised oxygen availability and mitochondrial dysfunction. Inspired by a modern factory, where both energy supply and equipment maintenance are essential for continuous production, a nanozyme-augmented energy-sustainable and oxidative-tolerant nanofactory of therapeutic proteins (NENFpro) has been developed. NENFpro is constructed by integrating the pOTUD1 (plasmid encoding the anti-inflammatory deubiquitinase OTUD1) and biocatalytic iridium nanozyme (IrNZ) into the nanosized zeolitic imidazolate framework-8 (ZIF-8) scaffold. Benefiting from the excellent antioxidant capacity of the incorporated IrNZ, the structure and bioactivity of plasmid drugs are well maintained in the destructive inflammatory microenvironment with excessive reactive oxygen species (ROS). Moreover, IrNZ can catalytically generate oxygen and prevent mitochondrial damage, thereby supplying sufficient energy for the transcription process of plasmid-based drugs to produce anti-inflammatory OTUD1 for IBD treatment. This nanozyme-engineered nanofactory of therapeutic proteins represents a desirabl strategy for the in situ long-acting therapy of chronic IBD.