Fibroblastic Reticular Cell–Derived and CD5L-Enriched Exosomes Remodel Renal Lipid Metabolism in Porcine Sepsis–Associated Acute Kidney Injury

Background: Sepsis-associated AKI is a life-threatening condition associated with profound metabolic dysfunction, including impaired mitochondrial fatty acid handling. Therapies capable of reversing this metabolic dysfunction remain lacking. Using a clinically relevant porcine model, we investigated whether kidney-targeted fibroblastic reticular cell-derived and CD5L-enriched exosomes could ameliorate sepsis-associated AKI. Methods: We generated engineered exosomes derived from fibroblastic reticular cells or CD5L-overexpressing cells and functionalized them with the kidney-targeting LTH peptide. Therapeutic efficacy and safety were evaluated in a porcine model of lipopolysaccharide-induced sepsis-associated AKI. Integrated multiomic and cellular analyses were performed to examine the associated molecular pathways. Results: In septic pigs, both fibroblastic reticular cell-derived and CD5L-enriched exosomes improved systemic hemodynamics, renal microvascular perfusion, and kidney injury indices. Exosome treatment reduced renal lipid-droplet and acylcarnitine accumulation. CD5L interacted with fatty acid synthase, and treatment was associated with changes in short-chain fatty acids and AMPK-ACC-CPT1A signaling. These lipid-metabolic changes were accompanied by improved mitochondrial bioenergetic indices, preserved mitochondrial morphology, and reduced markers of tubular cell pyroptosis. Conclusions: Kidney-targeted fibroblastic reticular cell-derived and CD5L-enriched exosomes produced comparable improvements in kidney injury indices and were associated with renal lipid-metabolic and mitochondrial remodeling in a large-animal model of sepsis-associated AKI.