A Robust Aqueous Core–Shell–Shell Coconut-like Nanostructure for Stimuli-Responsive Delivery of Hydrophilic Cargo

Conventional delivery systems for hydrophilic material still face critical challenges toward practical applications, including poor retention abilities, lack of stimulus responsiveness, and low bioavailability. Here, we propose a robust encapsulation strategy for hydrophilic cargo to produce a wide class of aqueous core-shell-shell coconut-like nanostructures featuring excellent stability and multifunctionality. The numerous active groups (-SH, -NH2, and -COOH) of the protein-polysaccharide wall material enable the formation of shell-cross-linked nanocapsules enclosing a liquid water droplet during acoustic cavitation. A subsequent pH switch can trigger the generation of an additional shell through the direct deposition of non-cross-linked protein back onto the cross-linked surface. Using anthocyanin as a model hydrophilic bioactive, these nanocapsules show high encapsulation efficiency, loading content, tolerance to environmental stresses, biocompatibility, and high cellular uptake. Moreover, the composite double shells driven by both covalent bonding and electrostatics provide the nanocapsules with pH/redox dual stimuli-responsive behavior. Our approach is also feasible for any shell material that can be cross-linked via ultrasonication, offering the potential to encapsulate diverse hydrophilic functional components, including bioactive molecules, nanocomplexes, and water-dispersible inorganic nanomaterials. Further development of this strategy should hold promise for designing versatile nanoengineered core-shell-shell nanoplatforms for various applications, such as the oral absorption of hydrophilic drugs/nutraceuticals and the smart delivery of therapeutics.