MMP-Activated Liposomal Nanoplatform Co-loaded with Kaempferol and ICG for Targeted Imaging and Therapy of Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disorder characterized by excessive oxidative stress, chronic inflammation, and extracellular matrix (ECM) degradation. Despite its high prevalence and poor clinical outcomes, no effective pharmacological therapies currently exist. Here, we developed a theranostic liposomal nanoplatform co-loaded with kaempferol (KPF), a natural flavonoid with potent anti-inflammatory and antioxidant activity, and indocyanine green (ICG), a photoacoustic imaging agent. The platform was surface-modified with an activatable cell-penetrating peptide (ACPP), a protease-cleavable cell-penetrating peptide that becomes active upon exposure to MMP-9 in AAA lesions, thereby enabling targeted delivery. The resulting formulation (ICG-KPF@ALNPs) exhibited selective accumulation in aneurysmal tissues and produced strong photoacoustic signals in vitro and in vivo. Therapeutically, ICG-KPF@ALNPs markedly reduced reactive oxygen species (ROS), suppressed inflammatory cytokines, and preserved ECM integrity. Mechanistically, kaempferol exerted a dual protective effect by activating the Nrf2/HO-1 pathway to scavenge ROS and inhibiting the NLRP3 inflammasome to limit macrophage pyroptosis, collectively mitigating oxidative stress and inflammation. These findings highlight ICG-KPF@ALNPs as a promising nanotheranostic strategy for noninvasive imaging and targeted treatment of AAA.