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

作者：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 · 发表于：Small · 年份：2026 · DOI：10.1002/smll.74813 · 研究领域：Retinal Diseases and Treatments、Ocular Diseases and Behçet’s Syndrome、Retinal Development and Disorders

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...