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

Abstract 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 mm³) 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.