Therapeutic modulation of the vitreoretinal fibrosis microenvironment in female mice using engineered macrophage-derived extracellular vesicles

Abstract Vitreoretinal fibrosis, a hallmark of proliferative vitreoretinopathy (PVR) triggered by retinal detachment or ocular trauma, necessitates surgery. Through data mining of the vitreoretinal fibrosis microenvironment in PVR patients and mice, showing elevated transforming growth factor β1 (TGFβ1) and M2 macrophage enrichment, we designed and engineered extracellular vesicles that conferred anti-fibrotic efficacy against PVR. These M1 macrophage-derived vesicles (M1evs) were conjugated with anti-TGFβ1 antibodies (aT) via MMP-cleavable linkers (aT-cl-M1ev, termed ACE). Upon intravitreal injection in female PVR model mice, ACE selectively accumulates in lesions, where released antibodies neutralize TGFβ1 and M1evs inhibit M2 macrophage polarization, modulating the microenvironment to diminish vitreoretinal fibrosis. Further incorporating anti-platelet-derived growth factor receptor antibodies yields aTP-cl-M1ev (ACE Plus ) to prevent retinal detachment progression in advanced-stage PVR, an efficacy validated in a patient-derived PVR membrane xenograft model. Therapeutic modulation of the vitreoretinal fibrosis microenvironment with the ACE platform provides an efficacious alternative to surgery for PVR.