Disrupting Complement‐Inflammation Positive Feedback Circuit via Oligonucleotide Hydrogel Microspheres for Reversing Joint Inflammation

Abstract The positive feedback circuit between the complement system and inflammatory immune responses maps the malignant progression of chronic joint inflammation. Prolonged dysregulation of the immune microenvironment in rheumatoid arthritis (RA) further exacerbates sustained complement activation, thereby establishing a vicious cycle. In this study, MMP‐9‐responsive, injectable micro‐nano geneplexes (C5ASO@HAP‐CL‐TIMP@HMs) are developed for on‐demand regulation of complement component C5, aiming to disrupt this pathological circuit. C5 antisense oligonucleotides (C5ASO) are loaded into cationic liposomes, which are subsequently encapsulated within hyaluronic acid microspheres via click chemistry. In vitro, these geneplexes effectively block abnormal C5 activation in RA synoviocytes, restore macrophage polarization balance, reduce pro‐inflammatory cytokine levels and immune complex precursor molecules, and upregulate anti‐inflammatory mediators. In an adjuvant‐induced arthritis rat model, they significantly alleviate joint swelling and cartilage degradation and suppress inflammatory responses, further highlighting the therapeutic potential of geneplexes in dismantling the complement‐inflammation circuit. In summary, the development of micro‐nano geneplexes capable of precisely disrupting the complement‐inflammatory circuit in RA offers a promising new perspective for the targeted treatment of chronic joint inflammation.