In situ bioorthogonal anchoring of stem cells to conductive nanofibrils for enhanced myocardial infarction repair.

Numerous efforts have been made to recover damaged myocardial infarction tissue with stem cells; however, poor differentiation and low viability of transplanted cells impede effective recovery of cardiac performance. We surface-engineered polymeric nanofibrils (NFs) to be electrically conductive and bioorthogonal click chemistry-reactive to improve the anchorage and performance of cardiac stem cells. Electrospun polycaprolactone nanofibers were hydrolyzed into NFs, followed by layer-by-layer coating with branched polyethylenimine and graphene oxide. The decorated NFs were then functionalized with a dibenzocyclooctyne (DBCO) group to endow them with azide (AZ) reactivity, and were subsequently reduced to retrieve electrical conductivity. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were functionalized with AZ groups via metabolic glycoengineering of unnatural N-azidoacetylmannosamine-tetraacylated (Ac4ManNAz), rendering it capable of DBCO reactivity. The DBCO-conjugated, reduced graphene oxide-decorated NFs (preClick-rGO@NFs) and preClick-CMs were co-injected as a freshly mixed suspension into the myocardial infarction area, where cell-NF complexes formed in a manner consistent with bioorthogonal coupling. This approach improved early retention of the implanted cells within the infarcted myocardium and enhanced recovery of cardiac function. Thus, we envision that surface-decorated powdery NFs and cell transplantation can contribute to improved cardiac performance through a simple surgery.