Biomimetic carrier-free nanoplatform based on natural polyphenols and siRNA for targeted therapy in rheumatoid arthritis

Rheumatoid arthritis (RA) is an auto-immune disease characterized by the excessive production of pro-inflammatory factors siRNA-mediated RNA interference offers a promising alternative owing to its high specificity and minimal side effects. However, the current cationic gene delivery system has always suffers from systematic toxicity due to excess cationic groups in the carrier. To overcome this drawback, we introduced a biomimetic siRNA delivery system with no cationic moiety, EHPS, using epigallocatechin gallate (EGCG) to condense TNF-α siRNA through hydrogen bonding, electrostatic interactions, and hydrophobic forces for the treatment of RA. Additionally, we enhanced this system with M1 macrophage membrane (M1m)-coated nanoparticles (termed M−EHPS) to evade the immune system and selectively target inflammatory cells. This design improved nanoparticle stability through additional hydrogen and hydrophobic bonding and reduced toxicity caused by conventional cationic carriers. M−EHPS could respond to high concentration of reactive oxygen species (ROS) in RA, facilitating rapid siRNA release from lysosomes via the proton sponge effect. Critically, this nanosystem also released EGCG, which mitigated a broad spectrum of reactive oxygen and nitrogen species (RONS), thereby creating a synergistic effect with siRNA. In RA mice model, intravenous administration of M−EHPS achieved targeted accumulation in inflamed joints and demonstrated potent anti-RA efficacy. This novel siRNA delivery system, integrating triple-interaction stability and intrinsic self-destructive release capability, presents a robust and efficient approach for targeted RA therapy and has significant potential for advancing RNA interference therapeutics in other diseases.