Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that requires long-term pharmacological management. Melittin, a peptide derived from bee venom, has shown promising therapeutic efficacy for RA by modulating immune balance. Given the critical role of the gut in immune regulation, oral administration of melittin could have significant clinical implications. However, this approach faces substantial challenges, including degradation by gastric fluids and off-target adverse effects, which compromise its efficacy and safety. To address these limitations, we developed an innovative orally administered, gut-targeted micro-nano system (SPM/AlgL) inspired by bacterial colonies. Herein, gas-shearing microfluidics is leveraged to monodisperse sialic acid-decorated peptide nanomedicines within calcium alginate microgels. These microspheres are then coated with probiotic biofilms, leveraging their acid resistance and intestinal adhesion properties. The biofilm coating effectively protects melittin from gastric degradation and enhances its accumulation in the mesenteric lymph nodes, thereby improving its targeting ability to inflammatory sites and reducing adverse effects. By modulating the Th1/Th2 and Th17/Treg ratios in the mesenteric lymph nodes and spleen tissues, this system successfully alleviates immune responses and efficiently mitigates the progression of arthritis. Overall, this oral therapeutic strategy demonstrates significant potential for advancing the immunotherapy of RA and other systemic autoimmune diseases.

Micro-nano system  /  Nanomedicines  /  Melittin  /  Rheumatoid arthritis  /  Oral administration  /  Hydrogel microspheres  /  Autoimmune diseases  /  Peptide delivery