Antibody-sheltered immunological nanonut (AINUT) for rheumatoid arthritis-targeted efficient alleviation

Therapeutic antibodies have realized substantial clinical benefits in alleviating rheumatoid arthritis (RA) development, yet suffer formidable challenges related to their proteolytic degradation in biological circumstances. A characteristic feature in the progression of RA is the dysregulated immune landscape that is essentially orchestrated by the inflammatory macrophages in arthritic joints. In this study, we confined the anti-TNF- α antibody (TNFi) into zeolitic imidazolate framework-8 (ZIF8) that was enveloped into nanosized vesicles derived from anti-inflammatory macrophages (M 2 NVs), obtaining anti-TNF- α antibody-sheltered immunological nanonuts (AINUTs). Both immunoassay and SDS-PAGE analyses demonstrated the nutshell-like protection of ZIF-8 to the confined TNFi with preserved structural integrity and biological activity even under the constant challenge of proteinase. The envelope of M 2 NVs were also verified as an optimal anti-inflammatory immune modulator that can regulate the immune landscape by reprogramming the pro-inflammatory macrophages toward the immunosuppressive subtypes. Therapeutic evaluations in a RA mouse model demonstrated that AINUTs were able to efficiently alleviate RA progression by remodeling the immune microenvironment and selectively releasing the initially sheltered TNFi to neutralize TNF- α in arthritic joints. This bio-preservation immune-regulating approach can reinforce the benefits of advanced biologics and be potentially extended to various therapeutic proteins for other inflammatory diseases. • An anti-TNF- α antibody showed well preserved biological activity because of the nutshell-like protection of ZIF-8. • M 2 NVs were verified to modulate the immune landscape of the RA microenvironment and realize inflammation remission of RA. • AINUTs can realize potent RA alleviation by remodulating the immune landscape and neutralizing TNF- α in arthritic joints.