Bioinspired Cardiac-Targeted Metal-Organic Framework Nanozyme for Modulating Inflammatory Responses in Heart Failure with Preserved Ejection Fraction

Zhen Li^1*Yuesheng Gui²Junyue Xing³Xiaowan Fan⁴Kairui Xiao¹Zongfeng Niu¹Yingying Wang²Weining Yuan¹Jia Shen²Yingchao Shi¹Xiaolei Cheng¹Yu Han^1*Hao Tang^1*

• ¹Fuwai Central China Cardiovascular Hospital, Zhengzhou, China
• ²Henan Provincial People's Hospital, Zhengzhou, China
• ³Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China
• ⁴Henan University Henan Medicine School, Kaifeng, China

Heart failure with preserved ejection fraction (HFpEF) is a common heart failure type with poor prognosis. Its mechanisms are unclear, and specific diagnostic criteria and effective treatments are lacking, hindering management. Recent studies highlight inflammation and oxidative stress in HFpEF. Anti-inflammatory interventions targeting oxidative stress show promise, but traditional antioxidants are insufficient. To address this, we designed a Mn-doping ZIF-8 nanozyme to mimic Mn SOD via biomimetic mineralization, potentially offering more effective and sustainable treatment for HFpEF. Mn-doping ZIF-8 is modified by ANP (NanoAM) and possesses significant cardiac targeting capability. It showed remarkable efficacy in improving cardiac diastolic dysfunction, lowering blood pressure, reducing cardiac fibrosis, and mitigating myocardial hypertrophy in HFpEF mice. NanoAM can also enhance cellular glucose uptake capacity by activating the SOCS3-IRS1-AKT2 signaling axis. NanoAM not only demonstrates its capacity to scavenge ROS but also suggests that it may exert dual therapeutic effects in the treatment of HFpEF by modulating insulin resistance signaling pathways. These findings provide new insights and potential intervention targets for the future clinical treatment of HFpEF.