Vascular Escape and Inflammation‐Targeted Therapy for Rheumatoid Arthritis Using Double‐Coated Radionuclide Aggregate Microspheres

ABSTRACT Radionuclide therapy directly eliminates diseased cells by inducing DNA double‐strand breaks; however, free radionuclides show poor targeting, are rapidly cleared by the mononuclear phagocyte system, and are quickly lost from highly perfused lesions such as joints due to capillary dilation, limiting retention and therapeutic efficacy. Here, we constructed a double‐coated radionuclide aggregate microsphere ( 131 I‐Au/RM@HM) using interface engineering. M2 macrophage and erythrocyte membranes were fused into hybrid vesicles, which were directionally assembled onto 131 I‐AuNPs via electrostatic interactions and stabilized by shear‐induced fusion and Au‐S chemical anchoring, forming a structurally robust dual envelope. The M2 membrane provides inflammation‐targeted recognition, while the erythrocyte membrane mediates immune evasion through CD47, and its highly glycosylated glycocalyx sterically hinders clearance by dilated capillaries. Loading 131 I‐Au/RM onto HAMA microspheres achieved efficient physical anchoring via the microsphere's three‐dimensional network and electrostatic interactions, forming radionuclide aggregates that generate high local concentrations through sustained release and synergistic radiosensitization by AuNPs. The system reduces clearance from dilated capillaries, selectively targets and efficiently eliminates M1 macrophages and inflammatory fibroblast‐like synoviocytes, suppresses pro‐inflammatory activity, and alleviates cartilage damage. This double‐coated, microsphere‐based strategy overcomes immune and vascular clearance of radionuclides, enabling long‐term local retention and precise delivery in chronic inflammatory diseases.