Pancreatic islet transplantation can restore insulin production in patients with severe diabetes, but donor material is scarce, and early engraftment is constrained by inflammatory and mechanical stress and a prolonged avascular phase, during which oxygen and nutrient delivery are limited by diffusion. Revascularization relies primarily on stress-induced vascular endothelial growth factor A (VEGF-A), prolonging metabolic compromise, increasing autophagic burden, and rendering grafts vulnerable to secondary stress. Accelerating vascular integration during this time window is therefore critical for graft health. We show that β-cell-targeted aptamer-VEGF-A small activating RNA (saRNA) chimeras selectively induce robust VEGF-A expression in mouse and human islets independently of hypoxia- or nutrient-stress pathways, without activating autophagy or stress-responsive genes. In vivo, chimera-primed islets transplanted into anterior chamber and kidney capsule models exhibited accelerated vascular migration, earlier perfusion, and faster resolution of LC3-dependent autophagic stress without altering endpoint vascular density. Functionally, marginal-mass mouse and human grafts restored glucose control more effectively, preserved intra-islet architecture, and delayed hyperglycemia following STZ-induced β-cell loss. The RNA chimera's modular architecture of RNA chimeras allows transient, tissue-adaptable transcriptional activation across species and cell sources. These findings establish that brief, ex vivo RNA-mediated priming preconditions islets to withstand early engraftment stress, enhancing vascular integration and functional outcomes. This scalable, stress-independent strategy may lower the minimum effective transplant mass and expand access to cellular therapies for diabetes.
