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There has been extensive interest in cellular therapies for the treatment of myocardial infarction, but bottlenecks concerning cellular accumulation and retention remain. Here, a novel system of in situ crosslinking mesenchymal stem cells (MSCs) for the formation of a living depot at the infarct site is reported. Bone marrow-derived mesenchymal stem cells that are surface decorated with heterodimerizing leucine zippers, termed ZipperCells, are engineered. When delivered intravenously in sequential doses, it is demonstrated that ZipperCells can migrate to the infarct site, crosslink, and show ≈500% enhanced accumulation and ≈600% improvement in prolonged retention at 10 days after injection compared to unmodified MSCs. This study introduces an advanced approach to creating noninvasive therapeutics depots using cellular crosslinking and provides the framework for future scaffold-free delivery methods for cardiac repair.