Cascade‐Amplified Light‐Free Singlet Oxygen Generation: A Biomimetic‐Targeted Nanogenerator for Precision Rheumatoid Arthritis Therapy

Abstract The aberrant proliferation of fibroblast‐like synoviocytes (FLSs) is a central driver of joint destruction and disease progression in rheumatoid arthritis (RA). Among reactive oxygen species (ROS), singlet oxygen ( 1 O 2 ) exhibits unique therapeutic potential due to its selective cytotoxicity toward hyperproliferative cells and its ability to overcome endogenous antioxidants. In this study, a light‐free 1 O 2 ‐generating nanogenerator CP@M is developed, constructed from platinum (Pt) clusters anchored on hollow nitrogen‐doped carbon spheres (CP) encapsulated with macrophage membranes (M) for the targeted elimination of pathogenic FLSs in RA. CP@M exhibits three unique therapeutic advantages: 1) Spontaneous 1 O 2 generation under light‐free conditions via superoxide‐mediated cascade reaction; 2) Self‐sufficient oxygen continuously supply enabled through catalase (CAT)‐like activity decomposing microenvironmental hydrogen peroxide (H 2 O 2 ); 3) Synergistic enhancement of 1 O 2 yield via NIR‐II responsive photothermal effect. Experimental results demonstrate that this cascade effect efficiently induces FLSs apoptosis, significantly inhibits bone and cartilage erosion, effectively blocks disease progression, and restores joint function. The light‐independent, self‐amplifying 1 O 2 generation strategy, combined with precise inflammatory targeting, provides a paradigm‐shifting new approach for RA therapy. This work not only proposes a novel class of biomimetic materials for self‐sustained 1 O 2 therapy but also establishes a transformative methodology for treating refractory inflammatory arthritis.