Carrier-free nanoparticles based on natural products trigger dual "synergy and attenuation" for enhanced phototherapy of liver cancer

Carrier-free nanoparticles have attracted significant interest owing to their exceptional drug-loading efficiency, simple preparation, and good biosafety. Inspired by the synergism and attenuation strategy of natural products, carrier-free nanoparticles were constructed from a compatibility perspective, aiming to carry natural products to tumor sites as nanoparticles to achieve precise anti-cancer effects. Herein, the carrier-free nanoparticles based on gambogic acid and glycyrrhizic acid (GG NPs) were successfully formed via self-assembly. The internally generated "synergism and attenuation" GG NPs could enhance the anti-tumor effect, reduce toxicity to normal cells, and exhibit tumor-targeting capabilities. Further, to explore the role of GG NPs in enhancing phototherapy, the photosensitizer ZnPc 2 was self-assembled with GG NPs to form GGZ NPs. <i>In vitro</i> studies demonstrated that the GGZ NPs significantly improved phototherapecutic efficacy. Compared with ZnPc 2, the photothermal conversion efficiency was increased to 80.8 %, along with a 1.8-fold increase in tumor growth inhibition, and the singlet oxygen yield of GGZ NPs increased by 2-fold. <i>In vivo</i> experiments demonstrated that GGZ NPs exhibit significant liver-targeting ability and could reduce the liver toxicity induced by gambogic acid, as well as decrease the blood biochemical levels of AST and ALT, achieving externally assisted "synergism and attenuation". Hence, carrier-free nanoparticles based on natural products would bring a new treatment modality to the field of precision liver tumor therapy.