Functional engineered exosomes mitigate pathological ischemic retinopathy through a dual strategy of inflammatory microenvironment modulation and angiogenic factor control

Retinal neovascularization (RNV), a major cause of blindness, is usually treated with anti-VEGF drugs. Despite successes, incomplete patient responses push for alternative strategies. In this study, a combined approach was devised by conjugating exosomes (Exo) derived from adipose mesenchymal stromal cells (ADMSCs) with specially designed peptides called KAI, using a cleavable linker controlled by matrix metalloproteinases (MMPs). This allowed for an environmentally responsive release of the peptide from Exo. Intravitreal injection of Exo resulted in the inhibition of pathological angiogenesis, accompanied by downregulation of immune response genes. Mechanistically, Exo were specifically phagocytized by microglia, resetting their activation status through the inhibition of the innate STING/NF-kappa B signaling pathway. Moreover, upon MMP stimulation in the retina, KAI was cleaved, effectively quenching multiple angiogenic factors simultaneously. This dual anti-inflammatory and anti-angiogenic strategy demonstrated significant therapeutic effects, including suppressed neovascularization, and reduced vascular leakage in the retina. Exo(KAI) treatment demonstrated no noticeable side effects, positioning these engineered nanodrugs as a promising alternative for ischemic retinopathy and refractory ocular neovascularization due to their combined effects.