Nose-to-Brain Inorganic Nanosystems for Alzheimer’s Disease Theranostics

Alzheimer’s disease (AD) presents a formidable therapeutic challenge due to the blood–brain barrier (BBB), which severely restricts central nervous system (CNS) access for systemically administered agents. Intranasal delivery offers a direct, non-invasive route to the brain parenchyma via olfactory and trigeminal pathways; however, its clinical efficacy is constrained by rapid mucociliary clearance and poor mucosal retention. While organic nanocarriers have been extensively reviewed, a critical knowledge gap remains regarding the dual diagnostic and therapeutic utility of inorganic nanosystems via the nose-to-brain route. This review specifically addresses this gap by analysing inorganic nanoscale platforms—including mesoporous silica, gold, silver, superparamagnetic iron oxide, quantum dots such as cadmium or carbon quantum dots and nanoceria—from a distinct theranostic perspective. We evaluate the key physicochemical parameters (surface chemistry, core morphology, and valence dynamics) that govern mucosal retention, epithelial transport, and brain bioavailability. Crucially, this review establishes a rigorous classification that explicitly distinguishes experimentally demonstrated theranostic platforms, concurrently integrating real-time bio-imaging with neuroprotective efficacy, from potential candidates that exploit therapeutic or diagnostic features in isolation. Furthermore, this work systematically details the parenchymal fate of inorganic platforms, focusing on pharmacokinetic bottlenecks, microglial sequestration, and glymphatic clearance dynamics. Recognizing that these advanced inorganic systems remain strictly within preclinical stages, we critically examine the translational landscape, outlining the key interspecies anatomical differences, chronic biopersistence constraints, and manufacturing scalability bottlenecks that currently impede clinical entry. By integrating recent toxicological constraints with green synthesis, Safety and Sustainability by Design (SSbD) frameworks and advanced surface engineering strategies, this review provides a dedicated framework for translating biocompatible, non-invasive inorganic theranostics into clinical applications for AD.