A macrophage plasma membrane-coated and DNA structured nanomedicine targets to alleviate rheumatoid arthritis via dual inhibition to TNF-α and NF-κB

High heterogenicity of rheumatoid arthritis (RA) leads to poor response in many patients. Combined therapies that simultaneously inhibit multiple proinflammatory targets may improve anti-RA efficacy. However, which monotherapies to combine and how to achieve the combination are critical issues. Here, we design a macrophage plasma membrane-coated and DNA structured nanomedicine to achieve a dual inhibitory therapy to Tumor necrosis factor alpha (TNF-α) and NF-κB. An anti-NF-κB decoy oligodeoxynucleotides (dODN) is first conjugated to a DNA cage with precise numbers and locations (Cage-dODN). Meanwhile, an anti-TNF-α siRNA is anchored to extracted macrophage plasma membrane (siRNA@M). Subsequently, siRNA@M is used to encapsulate Cage-dODN to fabricate siRNA@M(Cage-dODN) (siMCO). The size and zeta potential of siMCO are 63.1 ± 15.7 nm and -20.7 ± 3.8 mV respectively. siMCO shows increased intracellular uptake by inflamed macrophages and enhanced accumulation in inflamed mouse paws. siMCO also reduces pro-inflammatory factors at genetic and protein levels, alleviates arthritic symptoms, and shows no influence to major blood components. These results show that siMCO is a potential targeted, efficient, and safe dual inhibitory therapy for the treatment of inflammatory arthritis. The macrophage plasma membrane can be utilized to improve the targeting, stability, and efficacy of DNA structured nanomedicines.