Repairing the retinal ischemic microenvironment with an engineered exosome-loaded dehydroepiandrosterone peptide hydrogel

Abstract Retinal ischemia-reperfusion (RIR) injury creates a complex retinal pathological microenvironment (RPMe), contributing to vision-threatening diseases. Current research predominantly focuses on intracellular issues like oxidative stress and inflammation, while often neglecting extracellular matrix (ECM) fibrosis and angiogenesis. Here we developed an engineered exosome-loaded self-assembling peptide hydrogel to synergistically regulate both intracellular and extracellular events of RIR injury-induced RPMe. Engineered exosomes derived from retinal precursor cells, pre-treated with berberine and hypoxia, enhance cell repair and immune modulation. These exosomes are encapsulated in a hydrogel composed of dehydroepiandrosterone and insulin-like growth factor-I mimetic peptide, which not only possesses anti-inflammatory and antioxidant properties but also serves as a sustained exosome release system. Transcriptomic analysis reveals inhibition pathways including Wnt, PI3K/AKT (associated with oxidative stress and inflammation), and TGF-β/Smad3 and Notch3/Ang2 (related to ECM fibrosis and angiogenesis). Our multifunctional hydrogel provides a comprehensive treatment for retinal diseases by targeting both intracellular and extracellular RPMe events.