ZipperCells Exhibit Enhanced Accumulation and Retention at the Site of Myocardial Infarction

Abstract

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.

In Situ-Crosslinked Zippersomes Enhance Cardiac Repair by Increasing Accumulation and Retention

“…To enhance the accumulation and retention of intravenously injected EVs for the treatment of MI, we sought to create a second-generation approach to our ZipperCell platform with small nanosized EVs [39]. By utilizing heterodimerizing leucine zippers and decorating them on vesicle surfaces, we aimed to facilitate vehicle crosslinking, in situ.…”

Mechanisms and Barriers in Nanomedicine: Progress in the Field and Future Directions

“…In that way, the targeting surface can be continuously amplified to increase drug accumulation at the disease site. An interesting example was presented: boosting the targetable surface area through heterodimerizing leucine zippers, 109 which led to a substantial increase in accumulation and enhancement in prolonged retention. This pretargeting approach could be applied to different heterodimerizing ligands and carrier systems (i.e., micro-and nanoparticles) for enhanced accumulation and retention.…”

Advancing cell surface modification in mammalian cells with synthetic molecules

“…For instance, Jasiewicz et al employed sulfosuccinimidyl 4-( N -maleimidomethyl) cyclohexane-1-carboxylate (sulfo SMCC), a heterobifunctional crosslinker, to modify MSCs by covalently binding to the amines on the cell membrane and subsequently decorating them with heterodimerizing leucine zippers. 23 In addition, sulfo-NHS-biotin was also commonly utilized to modify the cell membrane where it serves as a “bridge” and facilitates the decoration of the cell membrane with cargoes through streptavidin–biotin interaction. 24–29 In addition to NHS ester derivatives, other types of reagents have been developed for covalently binding to –NH 2 including cyanuric chloride and benzotriazole carbonate.…”