Hyaluronic acid methacryloyl-based co-delivery system for aflibercept and miR-21-3p antagomir: a dual-therapeutic approach for diabetic retinopathy.

Diabetic retinopathy (DR) is a leading cause of vision loss characterized by concurrent retinal vascular dysfunction and neurodegeneration. While current therapies primarily target vascular dysfunction, they offer limited neuroprotective benefits. In this study, we developed a novel light-responsive hydrogel composed of hyaluronic acid methacryloyl (HAMA) for the co-delivery of aflibercept and miR-21-3p antagomir (HAMA@(Ab+M21A)). This dual-therapeutic strategy was designed to concurrently target retinal vascular dysfunction and neurodegeneration. Upon light exposure, HAMA hydrogel undergoes rapid in situ crosslinking, exhibiting excellent ocular biocompatibility and sustained drug release over 45 days, in parallel with controlled biodegradation. HAMA@(Ab+M21A) effectively inhibits VEGF-induced vascular dysfunction, suppresses reactive gliosis, and promotes retinal ganglion cell survival in vitro and in vivo. Collectively, this study demonstrates the therapeutic potential of HAMA@(Ab+M21A) as a dual-function strategy for DR, providing both anti-angiogenic and neuroprotective effects to impede disease progression.