A Peptide‐Drug Conjugate‐Based Nanoplatform for Immunometabolic Activation and In Situ Nerve Regeneration in Advanced‐Stage Alzheimer's Disease

Abstract The formidable protection of physiological barriers and unclear pathogenic mechanisms impede drug development for Alzheimer's disease (AD). As defenders of the central nervous system, immune‐metabolism function, and stemness of glial cells remain dormant during degeneration, representing a significant challenge for simultaneously targeting and modulating. Here, a modular nanoplatform is presented composed of peptide‐drug conjugates and an inflammation‐responsive core. The nanoplatform is transported through the blood‐brain barrier via transcytosis and disassembles in the oxidative stress microenvironment upon intravenous administration. The released drug‐conjugated modules can specifically target and deliver hydroxychloroquine (HCQ) and all‐trans retinoic acid (ATRA) to microglia and astrocytes, respectively. The immune function of chronic tolerant microglia is activated by metabolic modulation, and reactive astrocytes trans‐differentiate into functional neurons. In a transgenic mouse model, nanoplatform reduces levels of toxic proteins and inflammation while increasing neuronal density. This results in the amelioration of learning and memory decline. The modular nanoplatform provides design principles for multi‐cellular targeting and combination nano‐therapy for inflammation‐related diseases.