LAUSR

Nanoparticle drug delivery is largely restricted by the low drug loading capacity of nanoparticle carriers. To address this critical challenge and maximize the potential of nanoparticle drug delivery, a 2D ultra-thin layered double hydroxide (LDH) nanosheet with exceptionally high drug loading, excellent colloidal stability, and prolonged blood circulation for cancer treatment is constructed. The nanosheet is synthesized via a biocompatible polymer-assisted bottom-up method and exhibits an ultra-thin 2D sheet-like structure that enables a considerable amount of cargo anchoring sites available for drug loading, leading to an extraordinary 734% (doxorubicin/nanoparticle mass ratio) drug loading capacity. Doxorubicin delivered by the nanosheet remains stable on the nanosheet carrier under the physiological pH condition, while showing sustained release in the tumor microenvironment and the intracellular environment, thus demonstrating on-demand drug release as a result of pH-responsive biodegradation of nanosheets. Using in vitro and in vivo 4T1 breast cancer models, the nanosheet-based ultra-high drug-loading system demonstrates even enhanced therapeutic performance compared to the multilayered LDH-based high drug-loading system, in terms of increased cellular uptake efficiency, prolonged blood circulation, superior therapeutic effect, and reduced systemic toxicity.