Biomaterial-mediated scavenging of extracellular thrombospondin-1 in peripheral vessels mitigates intestinal ischemia-reperfusion injury

Intestinal ischemia-reperfusion (IR) injury presents as a severe condition characterized by microvascular dysfunction, epithelial barrier disruption, and systemic inflammatory responses, for which effective targeted therapies remain limited. Accumulating evidence indicates that pathological accumulation of extracellular matricellular proteins within ischemic microvascular niches critically amplifies oxidative stress and tissue damage during reperfusion. Here, we report a peptide-functionalized, biodegradable nanoplatform designed to selectively recognize and scavenge extracellular thrombospondin-1 (TSP-1) in ischemic intestinal peripheral vessels. LSKL-functionalized PEG-PLGA nanoparticles (LSKL/NPs) exhibit high affinity and stability in binding TSP-1 and preferentially accumulate within injured intestinal microvasculature following ischemia-reperfusion. By efficiently depleting pathological TSP-1, LSKL/NPs suppress TSP-1-mediated oxidative stress signaling, attenuate endothelial and epithelial apoptosis, and preserve vascular and intestinal barrier integrity. As a consequence, intestinal inflammation is markedly reduced, bacterial translocation is limited, and systemic inflammatory responses are alleviated, resulting in significant protection against distant organ injury. Importantly, LSKL/NPs demonstrate favorable biocompatibility and biosafety in vivo. Collectively, this study establishes a biomaterial-mediated extracellular protein scavenging strategy that mitigates intestinal ischemia-reperfusion injury by targeting pathological TSP-1 accumulation within peripheral vessels, offering a versatile and translationally promising nanotherapeutic paradigm for ischemic tissue protection. STATEMENT OF SIGNIFICANCE: This study reports a peptide functionalized, biodegradable PEG PLGA nanoparticle platform (LSKL/NPs) designed to scavenge extracellular thrombospondin 1 (TSP 1) for intestinal ischemia reperfusion injury (IRI). This focus is important because intestinal IRI is a devastating condition with limited effective therapies, and pathological extracellular mediators within ischemic microvascular niches remain insufficiently targeted. The work is significant because it defines a biomaterial driven mechanism in which LSKL/NPs preferentially accumulate in injured intestinal microvasculature and sequester extracellular TSP 1, thereby suppressing endothelial cell apoptosis and oxidative stress signaling, preserving endothelial and epithelial integrity, restoring barrier function, and reducing systemic inflammation and distant organ injury. Overall, this study establishes extracellular protein scavenging enabled by clinically validated, biodegradable materials as a generalizable therapeutic paradigm for ischemic tissue injury.