Rheumatoid arthritis —— Spleen-targeted mRNA nanoparticles regulate B cell overactivation in the treatment of rheumatoid arthritis

This article is selected:The therapy based on messenger RNA (mRNA) has become a revolutionary strategy to treat various diseases. In autoimmune diseases such as rheumatoid arthritis (RA), targeted mRNA delivery provides a potential intervention to regulate immune response. However, it is still challenging to realize the specificity and effective in vivo regulation of immunomodulatory factors (such as the inhibitory Fc γ receptor FcγRIIB) on B cells. In this study, lipid polymer nanoparticles (LPN) prepared from AMB-POC18 lipid and poly (ethylene glycol)-block-poly (lactide) (PEG-PLA) were designed to deliver FcγRIIB mRNA (mFcγRIIB) specifically to spleen B cells for RA treatment. The protein corona analysis showed that the selective adsorption of complement C3 on LPN surface promoted their targeted delivery to spleen, which improved the infection efficiency of B cells after intravenous administration. In the collagen-induced arthritis mouse model, mFcγRIIB/LPNs effectively up-regulated the expression of FcγRIIB in spleen B cells, significantly reduced the autoimmune response and alleviated RA symptoms. Further mechanism study shows that the increase of FcγRIIB expression inhibits B cell activation through FcγRIIB/Lyn/SHP-1 signaling pathway. This work emphasizes the potential of spleen-targeted mRNA delivery system for RA treatment, and provides an accurate and targeted method to regulate B cell activity and alleviate autoimmune diseases.

Innovations: 1. The spleen-targeted mRNA delivery system based on AMB-POC18 lipid and PEG-PLA was developed for the first time; 2. Innovatively utilize the selective adsorption of complement C3 on LPN surface to achieve spleen B cell targeting; 3. The mechanism that the increased expression of FcγRIIB inhibits the activation of B cells through a specific signal pathway was clarified. 4. The remarkable effect of mFcγRIIB/LPNs in the treatment of rheumatoid arthritis was systematically verified.

 Scientific research inspiration: 1. It shows the great application potential of mRNA therapy in autoimmune diseases; 2. Revealed the key role of nano-delivery system in precise immunomodulation; 3. A new strategy for organ-specific delivery of therapeutic mRNA is provided. 4. Proved the therapeutic value of precisely regulating immune cell function.

  Extension of ideas: 1. Explore the application of similar targeted delivery systems in other autoimmune diseases; 2. To compare the delivery efficiency of different types of mRNA nanocarriers; 3. Develop targeted delivery strategies for other immune cells; 4. Explore more applications of complement system in nano-drug delivery; 5. Deeply analyze the molecular mechanism network of B cell activation regulation; 6. Design a multifunctional immunomodulatory nano-delivery system; 7. To study the long-term safety of mRNA therapy in chronic inflammation.

DOI : 10.1002/adfm.202417101