Abstract
Myocardial ischemia/reperfusion injury with a high incidence of intramyocardial haemorrhage (IMH) contributes to enlarged infarct size by inducing additional cell death and predisposes to risk of heart failure. However, the risk factor in blood remains unverified and unaddressed. Here, we report that haem burstly released from IMH, is the key iron source for ferroptosis, and correspondingly propose the treatment strategy of blocking the cellular uptake of exogenous haem. Unfortunately, there is no existing haem-scavenging materials. We discover that methacryloyl modification of lysine residues on apo-lactoferrin (Apo-Lf), a milk-derived protein screen from natural haem-binding candidates, surprisingly increased the number of haem-binding sites by 86% and binding affinity by one order of magnitude. In animal models, intramyocardially implanted ferroptosis-inhibiting lactoferrin microsponges (FILMS) fabricated from the modified Apo-Lf achieved desirable anti-ferroptosis effects by rapid haem scavenging. Transcatheter FILMS implantation in pigs further demonstrated its safety and translational potential. These results provide deeper mechanistic understanding of ferroptosis-induced I/R injury, and may aid the development of other biomaterial-based therapies.