Microneedle Patch Loaded With Il-4 Macroparticles Facilitates Heart Repair Through Macrophages Mediated Cardiomyocyte Phenotype Transition

Ischemic heart disease remains the leading cause of mortality worldwide, but significant progress has been made in optimizing the treatment of acute myocardial infarction (MI) with percutaneous coronary intervention techniques. However, the increased pool of post-MI survivors has led to a higher prevalence of heart failure (HF) secondary to coronary artery disease, making it a major public health issue. Monocytes recruited from circulation differentiate into pro-inflammatory macrophages (M1-like) responsible for post-MI inflammation and cellular debris removal. As a unique Th2 cell cytokine, Interleukin 4 (IL-4) has been widely established as a powerful agent for the polarization of anti-inflammatory macrophages that promote tissue repair. However, there are limitations such as local and targeted delivery have hampered the successful translation of IL-4 therapy. In this study, we created an IL-4 microparticle-loaded microneedle patch (IL-4 MP-MN) for localized delivery of IL-4 to the MI region and tested the therapeutic effects in a rat model of MI. Our preliminary data suggested that IL-4 MP-MN treatment promoted cardiomyocyte proliferation and induced an anti-inflammatory microenvironment, which further led to a cardiomyocyte phenotype shift from "self-rescue" to "assisted-rescue" mode. Additionally, we successfully translated the therapeutic effects of IL-4 MP-MN in a porcine model of MI for testing therapeutic feasibility, safety, and efficacy.