Abstract 4367835: Macrophage-Targeted Theranostic Photoactivation Drives Inflammation Resolution and Stabilization of Atherosclerotic Plaques through Autophagy, Efferocytosis, and TGF-β-mediated Fibrotic Replacement

Introduction: Atherosclerosis is fundamentally driven by chronic, unresolved inflammation within arterial plaques. Photoactivation, which employs light-activated agents to generate reactive oxygen species and modulate local tissue responses, presents a promising theranostic strategy. However, its clinical translation has been limited by poor plaque targeting, insufficient tissue penetration, and lack of mechanistic understanding. We hypothesized that macrophage-targeted theranostic photoactivation, guided by intravascular multimodal imaging, could resolve plaque inflammation and induce stabilization through coordinated autophagy, efferocytosis, and TGF-β–mediated fibrotic remodeling. Method and results: We synthesized a macrophage-targeted, near-infrared-emitting photoactivatable agent by conjugating laminarin (a Dectin-1 ligand) with the photosensitizer chlorin e6 (LAM-Ce6). In atherosclerotic rabbit models, serial OCT-NIRF imaging confirmed that macrophage-targeted photoactivation markedly reduced inflammatory NIRF signals within plaques at 4 weeks post-laser irradiation. OCT analysis revealed that signal-poor regions with diffuse borders and signal-rich spots casting shadows transformed into homogeneous, high-backscattering areas, indicating reduced macrophage/lipid content and fibrotic remodeling. Mechanistically, photoactivation triggered early autophagy flux (LC3/LAMP2 colocalization) and induced macrophage apoptosis peaking at 1 day. This cascade promoted M2 macrophage polarization, upregulated MerTK expression, and enhanced efferocytosis, facilitating apoptotic debris clearance. Moreover, activation of the TGF-β/CTGF axis stimulated smooth muscle cell–mediated collagen synthesis, progressively converting lipid-rich plaques into fibrotic, stable lesions over 4 weeks. Together, these findings demonstrated sustained reductions in inflammatory activity and plaque burden on follow-up. Conclusion: Macrophage-targeted theranostic photoactivation guided by multimodal intravascular imaging effectively resolves inflammation and stabilizes vulnerable atherosclerotic plaques by orchestrating autophagy, efferocytosis, and TGF-β–driven fibrotic remodeling. This study provides mechanistic insights into phototherapy-induced plaque stabilization and highlights a promising catheter-based, imaging-guided therapeutic platform with strong translational potential for the personalized management of coronary artery disease.