A Sustainable Retinal Drug Co‐Delivery for Boosting Therapeutic Efficacy in wAMD: Unveiling Multifaceted Evidence and Synergistic Mechanisms

Abstract Sustainable retinal codelivery poses significant challenges technically, although it is imperative for synergistic treatment of wet age‐related macular degeneration (wAMD). Here, a microemulsion‐doped hydrogel (Bor/PT‐M@TRG) is engineered as an intravitreal depot composing of temperature‐responsive hydrogel (TRG) and borneol‐decorated paeoniflorin (PF) & tetramethylpyrazine (TMP)‐coloaded microemulsions (Bor/PT‐M). Bor/PT‐M@TRG, functioning as the “ammunition depot”, resides in the vitreous and continuously releases Bor/PT‐M as the therapeutic “bullet”, enabling deep penetration into the retina for 21 days. A single intravitreal injection of Bor/PT‐M@TRG yields substantial reductions in choroidal neovascularization (CNV, a hallmark feature of wAMD) progression and mitigates oxidative stress‐induced damage in vivo. Combinational PF&TMP regulates the “reactive oxygen species/nuclear factor erythroid‐2‐related factor 2/heme oxygenase‐1” pathway and blocks the “hypoxia inducible factor‐1α/vascular endothelial growth factor” signaling in retina, synergistically cutting off the loop of CNV formation. Utilizing fluorescence resonance energy transfer and liquid chromatography‐mass spectrometry techniques, they present compelling multifaceted evidence of sustainable retinal codelivery spanning formulations, ARPE‐19 cells, in vivo eye balls, and ex vivo section/retina‐choroid complex cell levels. Such codelivery approach is elucidated as the key driving force behind the exceptional therapeutic outcomes of Bor/PT‐M@TRG. These findings highlight the significance of sustainable retinal drug codelivery and rational combination for effective treatment of wAMD.