SIRT3-activating, biodegradable poly-honokiol with high drug loading for thoracic aortic dissection therapy

Introduction: Thoracic aortic dissection (TAD) is a life-threatening cardiovascular emergency with limited pharmacological treatment options.

Objectives: Building on the strong correlation between TAD and SIRT3 observed in our preliminary studies, we aim to leverage pharmacological interventions to enhance the clinical translation of this mechanism.

Methods: Based on the SIRT3 Activator honokiol, we synthesized a highly efficient, pH-responsive and biodegradable poly-honokiol prodrug synthesized via a metal-free phenol-yne click polymerization strategy, achieving an unprecedented drug-loading content of 83.65%, and subsequently investigated its pharmacological activity and underlying mechanisms using a β-aminopropionitrile (BAPN)-induced TAD model.

Results: Compared with honokiol, poly-honokiol markedly improved survival and reduced TAD incidence in mice by preventing vascular smooth muscle cell (VSMC) loss. Mechanistic investigations reveal that poly-honokiol activates the mitochondrial deacetylase SIRT3, which induce the deacetylation of both the antioxidant enzyme SOD2 and the key Ferroptosis regulator COX2, thereby reducing ferrous ion (Fe²⁺) accumulation and Reactive Oxygen Species (ROS) levels while suppressing mitochondrial permeability transition pore (mPTP) opening, ultimately attenuating ferroptosis-induced VSMC loss.

Conclusion: Collectively, these findings demonstrate that poly-honokiol is a potent preventive candidate for TAD, offering both high drug-loading efficiency and targeted mitochondrial protection.