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

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.