Photobiomodulation-reprogrammed extracellular vesicles delivered via a biodegradable microneedle patch promote cardiac repair by enhancing glycolytic metabolism.

Stem cell-derived extracellular vehicles (EVs) hold great therapeutic potential for myocardial infarction (MI). However, the efficient production of EVs with high bioactivity remains a critical bottleneck limiting their clinical translation. Here, we demonstrate that conditioned photobiomodulation (PBM) with green light is capable of activating human embryonic stem cells (hESCs) to secrete more EVs with superior cardioprotective activity. These PBM-reprogrammed hESC-EVs improve cardiac recovery in a murine MI model by promoting cardiomyocyte proliferation and angiogenesis while inhibiting apoptosis. Notably, we validate that these EVs similarly enhance the survival and proliferation of human cardiomyocytes, underscoring their translational potential. Further analysis reveals that this benefit is due to the higher miR-423-3p content in reprogrammed hESC-EVs, which enhances glycolytic metabolism and restores mitochondrial function by regulating the ZBTB7A/PKM2 axis. Moreover, we synthesize a methacryloyl hydrogel microneedle patch with superior biocompatibility, biodegradability, and mechanical strength for loading hESC-EVs, and convey the patch to the infarcted heart via a modified delivery apparatus. This system ensures the precise and sustained delivery of EVs to ischemic myocardium, offering a potent treatment for MI. Collectively, this optical and biomaterials-based approach efficiently prepares EVs with higher cardioprotective activity, providing new therapeutic strategies for heart disease.