Core-shell nanocarriers for brain delivery of dopamine and dopaminergic therapeutics: integrating materials design, electrochemical validation, and multiscale computational modelling

Dopaminergic dysfunction is a central feature of neurodegenerative and neuropsychiatric disorders, most prominently Parkinson’s disease (PD), with additional relevance for attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD). Direct therapeutic delivery of dopamine remains difficult because dopamine is chemically labile, rapidly metabolized in the periphery, and does not use an established endogenous transporter to cross the intact blood–brain barrier (BBB). L-DOPA presents a distinct delivery problem: it crosses the BBB through the large neutral amino acid transporter LAT1 but is susceptible to peripheral decarboxylation and catechol-O-methylation. These payload-specific differences preclude direct extrapolation between dopamine- and L-DOPA-loaded delivery systems. This review critically evaluates core–shell and related structured nanocarriers investigated for dopamine, L-DOPA, and selected dopaminergic therapeutics. The analysis covers mesoporous silica, biodegradable polymers, lipid-based systems, metal–silica constructs, metal–organic frameworks, and hybrid organic–inorganic interfaces. Particular emphasis is placed on how core and shell composition affect loading, chemical stability, release, nano–bio interactions, and experimentally measured transport endpoints. Evidence is classified as physicochemical, cellular, BBB-model-based, animal-based, or clinical, and endothelial association, model-barrier transport, brain-associated signal, pharmacodynamic benefit, and intact-carrier transcytosis are treated as distinct outcomes. Current evidence is strongest for formulation-dependent control of loading and release and, in selected systems, reduced dopamine oxidation. BBB-related evidence is more limited and heterogeneous: some polymeric and lipid formulations have been examined in endothelial models, and a smaller number of systems have produced brain-associated or pharmacodynamic effects in rodents. However, these findings do not generally establish delivery of an intact carrier to brain parenchyma, and no dopamine- or L-DOPA-loaded nanocarrier has yet demonstrated clinical efficacy. Electrochemical methods provide sensitive tools for studying dopamine redox chemistry and release, but evidence from endogenous dopamine sensing should not be interpreted as direct validation of a therapeutic nanocarrier. Similarly, computational approaches can generate testable hypotheses concerning interfacial binding, shell transport, release, and systemic disposition, but currently require formulation-specific experimental calibration. By integrating an evidence-based classification of the literature with payload-specific materials analysis, electrochemical validation, and multiscale modelling, this review identifies where experimental support is robust, where conclusions remain formulation- or model-dependent, and which validation steps are required before dopaminergic core–shell nanocarriers can be considered clinically competitive.