Antibody-sheltered immunological nanonut (AINUT) for rheumatoid arthritis-targeted efficient alleviation. (December 2022) - Liu, Lu
Abstract: 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 (M2 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 M2 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. Graphical Abstract: ga1 Highlights: An anti-TNF- α antibody showed well preserved biological activity because of the nutshell-like protection of ZIF-8. M2 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.