Targeted delivery of sinomenine hydrochloride using recombinant ferritin nanocages for rheumatoid arthritis treatment

Abstract

Rheumatoid arthritis (RA) is a chronic and refractory autoimmune disorder with high disability and teratogenic rates. The cause of RA remains elusive, and no specific treatment target has been identified yet. Natural sinomenine hydrochloride (SIN) has the potential to control the progression of RA. However, it suffers from limited bioavailability and unfavored biodistribution, leading to increased dosage and administration frequency, which in turn lead to adverse reactions. In this study, we engineered natural ferritin as a delivery vehicle for SIN, adding the CD24 functional fragment (Ser27-Gly59) on its surface (CD24-PfFn). Ferritin is highly biocompatible and exhibits passive targeting capability via the ELVIS effect. The attached CD24 on CD24-PfFn enables it to bind with immunosuppressive receptors Siglec-10 on the B cells and DAMPs in the pathological synovial fluid. This interaction results in both targeted accumulation of CD24-PfFn at the RA site and effective blockage of the downstream immune activation response, enhancing inflammation selectivity. With a simple depolymerization/self-assembly process, SIN could be effectively loaded into CD24-PfFn to form CD24-PfFn-SIN. Animal experiments showed that CD24-PfFn-SIN was highly selective for RA inflammatory joints and significantly restrained the progression of RA and repaired cartilage damage and bone erosion. Hence, this CD24-PfFn-SIN system represents a promising targeted therapy for RA treatment. Moreover, our ferritin modification strategy is verified, and this strategy is versatile as a large pool of functional peptides could be explored for other applications.