Lesion‐Localized Lubricating Microspheres Loaded with Highly Permeable Spermidine‐Derived Carbon Quantum Dots Attenuate Post‐Traumatic Ankle Osteoarthritis

ABSTRACT Post‐traumatic ankle osteoarthritis (PTOA) lacks effective conservative therapeutic strategies and requires the simultaneous mitigation of chronic inflammation, lubrication dysfunction, and progressive cartilage degeneration. In this study, spermidine‐derived carbon quantum dots (Spd‐CDs, SCD) were synthesized, and self‐healing lubricating microspheres were fabricated from aldehyde hyaluronic acid (AHA) and 2,2′‐diselanediyldiethanamine dihydrochloride (Sel). These microspheres (AHA+Sel, ASM) possess aldehyde‐functionalized surfaces that enable preferential localization to damaged cartilage, and exhibit intrinsic self‐healing capability through the synergistic effects of dynamic Schiff base bonds and diselenide bonds. Highly permeable SCD was subsequently encapsulated into ASM to construct a sustained‐release system (ASM@SCD). In vitro, SCD exerted pronounced anti‐inflammatory and antioxidative effects, inhibited chondrocyte ferroptosis, and restored dysregulated cartilage extracellular matrix metabolism. Mechanistically, bulk RNA‐sequencing combined with targeted lipidomics revealed that SCD enhanced ferroptosis resistance by promoting ACSL3‐dependent incorporation of monounsaturated fatty acids into plasma membranes, displacing polyunsaturated fatty acid‐containing phospholipids, and thereby reducing susceptibility to lipid peroxidation. In vivo, ASM@SCD treatment suppressed early cartilage degeneration and aberrant subchondral bone remodeling, improved joint function, preserved normal gait patterns, and significantly attenuated PTOA progression. Collectively, ASM@SCD represents a promising non‐surgical therapeutic strategy for PTOA.