Intravenous Multifunctional Nanotherapy for Treating Dry Age‐Related Macular Degeneration

Abstract Retinal pigment epithelium (RPE) degeneration is the pathological hallmark of multifactorial dry age‐related macular degeneration (dAMD). Mounting evidence implicates oxidative stress and aberrant activation of mammalian target of rapamycin (mTOR) as key drivers of this process. Recent studies have shown that simultaneous modulation of these pathways may offer therapeutic benefit. However, clinical trials of rapamycin, an mTOR inhibitor widely employed in retinal research, have demonstrated limited efficacy, potentially due to poor bioavailability and paradoxical effects on RPE and photoreceptors. To overcome these challenges, APMNP@Rapa, a rapamycin‐loaded, methionine‐based ROS‐responsive polymeric micellar system functionalized with an Ab peptide for active targeting of damaged RPE is developed. The micelles self‐assemble from poly(ethylene glycol) ‐ poly‐methionine copolymers, leveraging methionine's endogenous nature and innate biocompatibility as an innovative ROS‐responsive motif. This design yields particles with exceptional circulation stability and enhanced biocompatibility. In the high‐ROS microenvironment of diseased RPE, APMNP@Rapa triggers on‐demand rapamycin release. In a sodium iodate (NaIO 3 )‐induced RPE oxidative stress model, APMNP@Rapa simultaneously inhibited aberrant mTOR activation, attenuated oxidative damage, and suppressed inflammatory response. These combined effects resulted in a marked preservation of the retina against degradation. Overall, the research establishes a paradigm for intravenous treatment of dAMD using multifunctional nanotherapy.