Non-invasive co-delivery of Axitinib and telmisartan via LDH-based nanocarriers for synergistic VEGF/Ang-2 inhibition in ocular neovascular diseases

Neovascular ocular diseases are a leading cause of irreversible vision loss. Although intravitreal anti-VEGF therapy is the standard treatment, its invasive delivery and limited efficacy in some patients emphasize the need for non-invasive strategies targeting multiple angiogenic pathways. In this study, we developed a novel hybrid nanoplatform for the non-invasive co-delivery of axitinib (Axi) and telmisartan (Tel) to synergistically inhibit both VEGF and Ang-2 signaling pathways. Poorly soluble drugs were incorporated into layered double hydroxides (LDHs) via a micelle-assisted intercalation strategy and subsequently modified with hyaluronic acid (HA) conjugated to Gly-Val-Sar (GVS), a novel PepT1-targeted tripeptide. The Zn-containing LDH provided controlled drug release, and exhibited anti-inflammatory properties. HA modification prolonged ocular retention, and GVS enhanced transmembrane transport. The resulting Axi/Tel-D@LDH-HA-GVS nanocomposites demonstrated favorable physicochemical properties, efficient uptake by human conjunctival and retinal pigment epithelial cells, and potent inhibition of hypoxia-induced angiogenesis in vitro. In vivo, the formulations exhibited prolonged ocular retention, effective posterior tissue distribution, and good biosafety. In a diabetic retinopathy model, Axi/Tel-D@LDH-HA-GVS nanocomposites restored retinal structure and markedly reduced the expression of VEGF, Ang-2, TNF-α, and IL-6. Collectively, this study provides a promising non-invasive and synergistic strategy for targeted treatment of ocular neovascular diseases.