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 (M2NVs), 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 M2NVs 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.