Topically Delivered Treg‐Attracting Microparticle‐Hydrogel Composites Recruit Regulatory T Cells and Limit Cardiac Injury After Severe Ischemia

ABSTRACT Ischemic heart disease is a highly prevalent and debilitating condition throughout the world. Following an ischemic injury, the immune response can become overly active and spread damage to nearby healthy tissue. Because the heart lacks regenerative capacity, preventing excessive damage is critical. Existing immunosuppressive therapeutics provide indiscriminate suppression of inflammatory and repair functions of infiltrating immune cells. Regulatory T cells (Treg) are the body's highly sophisticated system for regulating immunologic activity. These cells can provide powerful immune suppression while amplifying repair pathways through direct stimulation of local cells. Our research group has previously developed a polymeric delivery system comprised of poly(lactic‐co‐glycolic acid) (PLGA) degradable microparticles (MP) loaded with the Treg‐attracting protein, CCL22. In our previous work, we demonstrated CCL22MP attracts Treg to the injection site and can suppress disadvantageous inflammation. Here we combine our Treg‐attracting MP technology with H ydrogels to E nhance or A ttract R egulatory T cells ( HEART ). Topically applied HEART significantly reduced infarct size and improved ejection fraction after permanent‐ligation MI, and in a cardiac transplant ischemia model reduced graft fibrosis while significantly increasing intragraft Foxp3 + Treg at 30 days. Efficacy tracked with injury severity, identifying severe ischemic injury as a setting where this therapeutic strategy may be most beneficial.