Hanan Mohammad, Maher Darwish, Gábor Katona, Ildikó Csóka
Albumin nanoparticles represent a unique protein-based platform for brain drug delivery, leveraging albumin intrinsic properties including exceptional biocompatibility, prolonged 19-day circulation half-life, and endogenous transport pathways via gp60 and FcRn receptors. While the blood-brain barrier restricts ∼98 % of therapeutic agents from reaching the central nervous system, functionalized albumin nanoparticles overcome this challenge by hijacking native transport mechanisms at the barrier interface. This review delivers an extensive evaluation of various methodologies for functionalizing albumin nanoparticles via covalent and non-covalent approaches aimed at improving barrier permeability, enhancing targeting precision, and enabling controlled drug release. Particular emphasis is given to ligand-based modifications that enable active receptor targeting and stimuli-responsive systems triggered by the brain microenvironment. Unlike reviews covering general nanocarrier systems, this work specifically focuses on the distinctive properties and functionalization strategies unique to albumin-based platforms. Albumin multiple reactive groups provide a versatile scaffold for functional ligand conjugation, distinguishing it from synthetic nanocarriers. Despite persisting challenges, including formulation consistency and clinical translation enhancement, functionalized albumin nanoparticles provide versatile solutions with promising advancements for treating brain tumors, neuroinflammatory disorders, and neurodegenerative diseases.