Molecular Stacking Composite Nanoparticles of Gossypolone and Thermodynamic Agent for Elimination of Large Tumor in Mice via Electrothermal-Thermodynamic-Chemo Trimodal Combination Therapy

To further improve the comprehensive therapeutic effect for large tumors, tumor cell membrane-camouflaged molecular stacking composite nanoparticles (APGn@Mem NPs) are prepared by molecular stacking of chemotherapeutic drug gossypolone (Gn), thermodynamic agent (2,2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH)), polyvinyl alcohol, and phase change material lauric acid, which show a clear core–shell structure with a size of 65 ± 9.8 nm, high drug loading, low toxicity, homologous targeting, and thermal-responsive release property. A type of micro-electrothermal needle (MEN) with precise temperature control in situ (temperature range: mean value T ± 7 °C) is designed as the assistant heating system for APGn@Mem NPs. Subsequently, an elaborate tumor combination therapy strategy of electrothermal-thermodynamic-chemo trimodal combination therapy is developed through APGn@Mem NPs combined with the temperature control of MEN. Under MEN heating in situ, AIPH is rapidly released and generates abundant free radicals for short-term electrothermal and thermodynamic therapy, while the release of Gn is relatively slow for long-term chemotherapy. For large tumors (≈300 mm 3 ) of nude mice, such combination therapy achieves remarkable comprehensive therapeutic efficacy with the 16-day tumor inhibition rate of 99.89% and the 60-day tumor recurrence rate of 20%, indicating this combination therapy has the prominent advantage and potential application in future.