Engineering exosomes for Alzheimer's disease: Multi-target therapeutic strategies from pathogenesis to clinical translation.

The complex pathogenesis of Alzheimer's disease (AD), combined with the presence of the blood‒brain barrier (BBB), severely limits the effectiveness of conventional therapeutic approaches. Engineered exosomes-nanoscale extracellular vesicles of natural origin-have emerged as a promising platform for innovative AD therapy due to their excellent biocompatibility, low immunogenicity and intrinsic ability to cross the BBB. This review provides a systematic overview of the synthetic and structural biological characteristics of exosomes, with a focus on their functionalisation through physical, chemical and genetic modifications. These approaches enable the targeted loading of therapeutic cargo and the conjugation of brain-targeting peptides, thereby facilitating precise delivery to specific brain regions and offering a multi-target therapeutic strategy for AD. We further examine the potential of engineered exosomes in modulating core AD pathological pathways, including amyloid-beta deposition, tau hyperphosphorylation, neuroinflammation and synaptic dysfunction, and highlight their utility as an integrated delivery system for the co-delivery of multiple therapeutic agents to achieve synergistic therapeutic effects. Finally, key challenges in clinical translation are addressed, such as scalable production, standardised drug loading protocols and comprehensive assessment of safety and immunogenicity. Unlike previous reviews that primarily focus on general engineering techniques, this article emphasises a rational design strategy tailored for multi-target synergistic therapy and presents a comprehensive roadmap from basic research to clinical application, thereby providing both theoretical insights and practical guidance for the development of next-generation AD treatments. KEY POINTS: A multidimensional approach combining physical, chemical, and genetic modifications equips exosomes with brain-targeted peptides, enhancing their capability for precise brain delivery in Alzheimer's disease (AD) Engineered exosomes are designed to cross the blood-brain barrier and provide stimuli-responsive release of therapeutic agents, enabling simultaneous clearance of amyloid-beta plaques and neurofibrillary tangles, and inhibition of neuroinflammation. The transition from preclinical success to early-phase human trials is underway, with intranasal administration emerging as a promising, non-invasive method for brain drug delivery. A well-defined plan for clinical translation includes scalable Good Manufacturing Practice (GMP) production, rigorous safety assessments, and biomarker-guided clinical trial design to facilitate clinical application.