Sustained Retinal Delivery of Baicalin and Ranibizumab Overcomes the Anti-VEGF Monotherapy Dilemma in wAMD.

Authors

Xi Jiang, Fengqi Yang, Huiling Gong, Yanfei Mou, Junyi An, Lei Wang, Xiaona Wang, Zhenzhen Zhang, Xiao Wei, Li Sun, Wenli Wang, Fenglei Cao, Yang Zhao, Ding Qu

Published in

Small (Weinheim an der Bergstrasse, Germany). Pages e74813. Jul 27, 2026. Epub Jul 27, 2026.

Abstract

Wet age-related macular degeneration (wAMD), characterized by choroidal neovascularization (CNV), faces a clinical challenge of diminishing efficacy during long-term anti-VEGF monotherapy. An AI-assisted analytical framework pinpointed impaired retinal pigment epithelium (RPE) autophagy and a pro-inflammatory microenvironment driven by retinal microglia-recruited monocytes as co-conspirators in CNV progression. To tackle these dual culprits, we developed an intravitreal injectable hydrogel (Rab&BCL-M@G) that co-encapsulates ranibizumab (Rab) and a small-sized baicalin-loaded microemulsion (BCL-M), enabling controlled and sustained co-delivery of both agents to the retina for over 14 days. Guided by the AI-identified targets, we demonstrated that baicalin promoted dysfunctional mitochondria clearance via the AKT2-PGC-1α-mediated autophagic flux and suppressed monocyte recruitment by disrupting microglial CCL4 signaling. This two-pronged action ameliorated inflammation and angiogenesis, synergizing with Rab. In a laser-induced wAMD mouse model, a single intravitreal injection of Rab&BCL-M@G sustainably reduced CNV area, promoted repair, restored autophagy, and diminished microglial infiltration. Crucially, subsequent wet-lab validation confirmed a positive pathological correlation among defective autophagy, inflammation, and angiogenesis, thereby closing the loop from computational prediction to experimental verification and explaining suboptimal long-term performance after Rab monotherapy. This study proposes a promising synergistic strategy, advancing wAMD therapy through precision delivery and AI-informed mechanism discovery.

PMID:
42504692
Bibliographic data and abstract were imported from PubMed on 27 Jul 2026.

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