Abstract

Mesenchymal stem cell (MSC)-derived exosomes show clear potential in cell-free regenerative medicine. However, their clinical translation is limited by low production yields and inconsistent therapeutic efficacy. To address this, we actively programmed stem cell apoptosis to generate high-yield, functional extracellular vesicles. By using deferoxamine (DFO) to stabilize HIF-1α prior to UV-induced apoptosis, we produced DFO-programmed apoptotic bodies (DABs). These programmed apoptotic bodies demonstrated a significantly higher production yield than conventional exosomes. Multi-omics analyses revealed that DABs inherit an enriched, pro-regenerative miRNA repertoire that functionally outperforms both native apoptotic bodies and exosomes. Beyond promoting classical angiogenic and migratory signaling, DABs support tissue repair by altering the mitochondrial bioenergetics of recipient cells. To prevent rapid in vivo clearance and address the highly oxidative diabetic microenvironment, we encapsulated DABs within a glucose- and ROS-responsive hydrogel, developing the DABs@PHA-PVA Gel . In vivo transcriptomics demonstrated that DABs@PHA-PVA Gel synchronized active ROS scavenging with the on-demand release of DABs. This localized delivery improved complete tissue reconstruction by simultaneously enhancing the Cxcr4/Nrp1/S1pr1 angiogenic axis, activating the Daglb/Cnr2 anti-inflammatory pathway, and engaging the Txnip/Foxo4/Nrf2 antioxidant cascade. Overall, this study establishes programmed apoptotic bodies as a scalable and effective alternative to standard exosome therapies for tissue regeneration. Graphical abstract