Abstract
<title>Abstract</title> <p>Myocardial infarction (MI) triggers an acute burst of reactive oxygen species (ROS) that induces cardiomyocyte death, followed by persistent fibrotic remodeling, ultimately leading to irreversible heart failure. Conventional reperfusion and systemic pharmacotherapy fail to address both acute oxidative injury and chronic fibrosis simultaneously, and are often associated with substantial off-target toxicity. Black phosphorus nanosheets (BPNs) possess broad-spectrum ROS-scavenging and mitochondrial protective properties, whereas bufalin (Buf) is a potent natural anti-fibrotic agent. However, their clinical translation is hampered by poor myocardial accumulation, low aqueous solubility, and bufalin-related arrhythmogenic risks upon systemic administration. To overcome these barriers, we developed a ROS-responsive core-shell microneedle patch (BPNs/Buf@MNs) that enables minimally invasive epicardial co-delivery of the two agents. The outer hyaluronic acid-phenylboronic acid (HA-PBA) hydrogel shell, loaded with BPNs, undergoes ROS-triggered degradation in the infarct zone to release nanosheets for immediate antioxidant protection, while the inner gelatin methacryloyl (GelMA) core ensures sustained bufalin release to suppress long-term fibrotic scarring. This hierarchical architecture achieves spatiotemporally sequential cargo release, matching the biphasic pathological progression of MI. In vitro, BPNs/Buf@MN extracts reversed oxygen-glucose deprivation (OGD)-induced cardiomyocyte redox imbalance, stabilized mitochondrial ultrastructure, and blocked TGF-β-stimulated activation, proliferation and migration of cardiac fibroblasts. In a murine MI model, epicardial implantation of BPNs/Buf@MNs maintained myocardial drug retention for 14 days, reduced infarct size, restored systolic function, normalized collagen deposition, reconstructed microperfusion, and mitigated epicardial-thoracic adhesions. Mechanistically, the patch suppressed inflammatory cascades, upregulated Connexin 43 (CX43), attenuated cardiomyocyte hypertrophy, and preserved mitochondrial integrity. Systematic biosafety assessments confirmed complete biodegradability and no obvious organ toxicity over 28 days. Transcriptomic analysis further revealed global repression of pathological programs related to extracellular matrix remodeling, inflammation and oxidative stress. This stimulus-responsive core-shell microneedle platform offers a safe, minimally invasive combinatorial nanomedicine strategy for MI treatment and expands the cardiovascular application scope of black phosphorus two-dimensional nanomaterials.</p>