Metal Phenolic Network‐Integrated Multistage Nanosystem for Enhanced Drug Delivery to Solid Tumors

Metal‐phenolic networks (MPNs) are an emerging class of supramolecular surface modifiers with potential use in various fields including drug delivery. Here, the development of a unique MPN‐integrated core‐satellite nanosystem (CS‐NS) is reported. The “core” component of CS‐NS comprises a liposome loaded with EDTA (a metal ion chelator) in the aqueous core and DiR (a near‐infrared photothermal transducer) in the bilayer. The “satellite” component comprises mesoporous silica nanoparticles (MSNs) encapsulating doxorubicin and is coated with a Cu2+‐tannic acid MPN. Liposomes and MSNs self‐assemble into the CS‐NS through adhesion mediated by the MPN. When irradiated with an 808 nm laser, CS‐NS liberated the entrapped EDTA, leading to Cu2+ chelation and subsequent disassembly of the core‐satellite nanostructure. Photo‐conversion from the large assembly to the small constituent particles proceeded within 5 min. Light‐triggered CS‐NS disassembly enhanced the carrier and cargo penetration and accumulation in tumor spheroids in vitro and in orthotopic murine mammary tumors in vivo. CS‐NS is long circulating in the blood and conferred improved survival outcomes to tumor‐bearing mice treated with light, compared to controls. These results demonstrate an MPN‐integrated multistage nanosystem for improved solid tumor treatment. Upon 808 nm laser irradiation, DiR‐mediated photothermal effect leads to the instability of “core” liposomes, and triggers EDTA release to chelate the Cu2+ from the metal phenolic networks. This effect disassembles the core‐satellite nanosystem to liberate the satellites for enhanced penetration and chemotherapy.