Suppressing angiogenic phenotypes in retinal cell models through light-triggered anti-VEGF release from upconversion nanoparticle-loaded chitosan microgels

Anti-VEGF injections are effective for neovascular age-related macular degeneration (nAMD) but require frequent intravitreal dosing and provide limited spatiotemporal control. We engineered injectable chitosan-methacrylate (ChiMA) microgels that co-localize upconversion nanoparticles (UCNPs) with a photocaged anti-VEGF peptide to enable on-demand, near-infrared (980 nm)-triggered release. Colloidal UCNPs (β-NaYF₄: Yb,Tm core/shell) were synthesized via a thermal decomposition method and subsequently embedded into visible-light-crosslinked ChiMA microgels together with a nitrobenzyl-linked anti-VEGF peptide. We quantified microgel morphology, swelling and injectability, peptide loading/release under near infra-red (NIR) irradiation (20 mW/cm²) and durations (30 min), and cytocompatibility in MIO-M1, RPE-1, and HUVEC cells. Anti-angiogenic activity was assessed by VEGF-driven scratch migration, tube formation, and signaling (HIF-1α, p-Akt, p-p38, occludin, ZO-1). Microgels with 10 wt% UCNPs showed the most efficient NIR-triggered release around 85%. Cytocompatibility assays indicated approximately 90% viability for UCNPs-loaded microgels, consistent with minimal cytotoxicity. In vitro, NIR irradiation of anti-VEGF-peptide-functionalized ChiMA microgels reduced endothelial migration and tube formation by 20% and 15%, respectively, relative to VEGF-stimulated controls. VEGF-responsive signaling was concomitantly decreased by 50%, and Akt phosphorylation was likewise halved compared to VEGF alone. These findings indicate that UCNPs-loaded ChiMA microgels enable non-invasive, repeatable, on-demand peptide delivery and attenuate pro-angiogenic pathways, supporting subsequent in vivo evaluation.