TLR2 inhibition attenuates NET-driven inflammation and restenosis during poly-lactic acid bioresorbable scaffold degradation.

Poly-lactic acid (PLA) bioresorbable scaffolds provide temporary vascular support but trigger late-stage inflammation during polymer dissolution, frequently driving neointimal hyperplasia before complete dissolution. While acute biomaterial responses are well documented, the innate immune mechanisms dictating chronic vascular remodeling remain poorly defined. We demonstrate that late-stage PLA degradation actively instructs a microenvironment dominated by neutrophil extracellular trap (NET). Combining transcriptomic profiling of stented porcine arteries, and longitudinal spatial histology, we mapped a sustained immune response directly coupled to polymer breakdown. Mechanistically, PLA degradation products induce NET extrusion via mitochondrial calcium uniporter-mediated calcium overload. These extracellular structures subsequently function as potent paracrine signals, driving human vascular smooth muscle cells (VSMCs) toward a proliferative, synthetic phenotype. We identified a toll-like receptor 2 (TLR2) signaling pathway as the primary transducer of this NET-driven VSMC reprogramming. To apply these findings therapeutically, we engineered a customized PLA scaffold coated exclusively with the selective TLR2 inhibitor C29. In a rabbit iliac artery model, this targeted immunomodulatory device successfully disrupted the local inflammatory loop, significantly reducing neutrophil accumulation and mitigating neointimal hyperplasia. This study establishes the biomaterial-driven NET-TLR2 axis as a central mechanism of adverse vascular remodeling and offers a precise bioactive strategy to preserve long-term luminal patency.