A Biomimetic Nanoparticle System Intercepts and Degrades Thrombospondin‐1 to Restore Vascular Homeostasis After Ischemic Injury

ABSTRACT The thrombospondin‐1 (TSP‐1)/CD47 signaling axis plays a critical role in endothelial injury during hepatic ischemia‐reperfusion (IR). Targeting this pathway represents a promising strategy to prevent liver IR injury; however, existing CD47 antagonists cause severe hematologic side effects due to nonspecific binding to erythrocytes. This study developed TAX2 (CD47‐derived peptide with the sequence CEVSQLLKGDAC)‐functionalized biodegradable nanoparticles (TAX2‐NPs) that specifically capture TSP‐1 and block its interaction with CD47 on liver sinusoidal endothelial cells (LSECs). TAX2‐NPs are composed of PLGA and DSPE‐PEG‐Mal and are conjugated with the cyclic peptide TAX2, derived from the TSP‐1‐binding domain of CD47. Upon systemic administration, TAX2‐NPs preferentially accumulate in the injured liver, where they competitively bind TSP‐1, preventing endothelial apoptosis and preserving sinusoidal integrity. Captured TSP‐1 is subsequently internalized by macrophages and degraded via the autophagy‐lysosome pathway, thereby eliminating residual extracellular TSP‐1 and mitigating its prolonged pathogenic effects. Collectively, this study presents a ligand‐targeted nanotherapeutic strategy that integrates TSP‐1 sequestration, signaling blockade, and autophagy‐mediated degradation, offering a safe and effective approach to protect the liver from ischemia‐reperfusion injury.