Engineering Gold Nanocages for Precision Drug Delivery: From Structural Design and Stimuli-Responsive Release to Theranostic Applications

Gold nanocages (AuNCs) are hollow, porous plasmonic nanostructures featuring an internal cavity for cargo accommodation, a gold-rich surface amenable to functionalization, and tunable near-infrared (NIR) optical properties, enabling controlled delivery, photothermal activation, and imaging within a single platform. As AuNC research has evolved from galvanic-replacement synthesis and photothermal ablation toward stimuli-responsive and multifunctional systems, the central challenge has shifted from simply adding functions to achieving reproducible control of therapeutic exposure in space, time, and dose through coordinated structural and formulation engineering. This review examines the relationships among nanocage architecture, interfacial modification, cargo loading and retention, stimuli-responsive release, biological transport, therapeutic applications, and theranostic strategies ranging from imaging-enabled monitoring to imaging-guided intervention. Particular emphasis is placed on how particle size, wall thickness, porosity, cavity architecture, residual Au–Ag composition, surface state, and localized surface plasmon resonance influence loading capacity, release kinetics, optical energy deposition, cellular uptake, biodistribution, and biological fate. We further discuss how PEGylation, targeting ligands, responsive polymers, nucleic-acid gates, lipid layers, biomimetic coatings, and endogenous or exogenous stimuli can transform AuNCs from passive carriers into programmable delivery platforms. Across cancer, infection, inflammation, regeneration, and cardiovascular applications, precision delivery depends on coordinated control of localization, payload release, therapeutic exposure, and imaging-informed treatment decisions. Despite substantial progress, clinical translation remains constrained by challenges including reproducibility, residual silver, compositional heterogeneity, formulation stability, long-term gold retention, limited optical penetration, incomplete understanding of carrier and cargo fate, sterilization, manufacturing complexity, and scale-up. Future studies should prioritize quantitative structure–property–delivery relationships, formulation-level critical quality attributes, clinically relevant trigger thresholds and exposure ranges, and imaging-feedback workflows that demonstrate reproducible advantages over simpler delivery systems.