Designing blend polymersomes co-loaded with HRH peptide and sphingosine for the treatment of ocular neovascularization

Official URL: https://dx.doi.org/10.1016/j.jddst.2025.107156

Ocular neovascularization threatens millions around the world, and current anti-VEGF drugs could not satisfy the clinical needs. Polymersomes, which could penetrate ocular barriers, have recently gained attention as ocular drug delivery systems. In our previous study, high therapeutic efficiency of HA-Sph polymersomes for ocular neovascularization was demonstrated with sphingosine-associated toxicity towards corneal cells. In this study, we developed a novel blend polymersome system composed of two hyaluronan-based amphiphilic polymers that decreases the final sphingosine concentration. The blend polymersomes were incorporated with a second anti-angiogenic compound (HRH peptide) along with sphingosine and exhibited size, zeta potential, and encapsulation efficiency of 141.3 ± 12.2 nm, −25.8 ± 6.2 mV, and 79.8 ± 6.8 %, respectively. The final blend polymersomes system released 35.2 % HRH peptide over a week and this amount is doubled (70.5 %) via enzymatic degradation. Notably, we found that HRH-loaded blend polymersomes significantly reduced the proliferation of HUVECs while not impacting the viability of retinal pigment epithelial and corneal cells. Moreover, in vitro tube formation was significantly reduced by using HRH-loaded polymersomes, compared to HRH alone and ranibizumab groups. The overall tube length was reduced by 29.6 % and 38.1 % compared to normal and excess VEGF controls, respectively. We further observed the self-targeting capability of polymersomes through uptake via CD44 receptors on endothelial cells. Overall, this dual-drug-loaded, blend polymersomes system introduces a safer and more effective alternative to previous HA-Sph platforms and presents a promising, non-invasive approach for treating ocular neovascularization.