β-cell-targeted RNA activation of vascular endothelial growth factor-A improves islet transplantation.

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.