Near infrared light triggered ternary synergistic cancer therapy via L-arginine-loaded nanovesicles with modification of PEGylated indocyanine green.

L-arginine (L-Arg) is an important nitric oxide (NO) donor, and its exploration in NO gas therapy has received widespread attention. Application of nano-platforms that can efficiently deliver L-Arg and induce its rapid conversion to NO becomes a predominant strategy to achieve promising therapeutic effects in tumor treatment. Herein, an enhanced nano-vesicular system of ternary synergistic treatment combining NO therapy, photodynamic therapy (PDT) along with mild photothermal therapy (MPTT) was developed for cancer therapy. We integrated photosensitizer PEGylated indocyanine green (mPEG-ICG) into polyphosphazene PEP nano-vesicles through co-assembly and simultaneously encapsulated NO donor L-Arg into the vesicle center chambers to form mPEG-ICG/L-Arg co-loaded system IA-PEP. The unique nanostructure of vesicle provided considerable loading capacity for mPEG-ICG and L-Arg with 15.9% and 17.95% loading content, respectively, and efficiently prevented mPEG-ICG and L-Arg from leaking. Significantly, the reactive oxygen species (ROS) was produced by IA-PEP under 808 nm laser irradiation to perform PDT against tumors, which concurrently reacted with L-Arg to release NO and arouse gas therapy effectively. Moreover, the mild heat produced by IA-PEP could exhibit cooperative anti-tumor effect with minimal damage. As a consequence, in vivo antitumor investigation on nude mice bearing xenograft MCF-7 tumors verified the potent anti-tumor efficacy of IA-PEP under 808 nm laser irradiation with complete tumor elimination. Taken together, the IA-PEP nano-vesicle system designed in this work may provide a promising treatment paradigm for synergistic cancer treatment. STATEMENT OF SIGNIFICANCE: Nitric oxide (NO) gas therapy has drawn widespread attention due to its "green" treatment paradigm with negligible side effects. L-arginine (L-Arg) is an important NO donor. However, how to efficiently deliver L-Arg and induce NO generation remains a big challenge since L-Arg is a water-soluble small molecule. Herein, we developed a nano-vesicle system IA-PEP to integrate photosensitizer PEGylated indocyanine green and L-Arg with high loading content and to produce a ternary synergistic treatment combining NO therapy, photodynamic therapy (PDT) along with mild-temperature photothermal therapy (MPTT) under 808 nm laser irradiation. The in vivo investigation on nude mice bearing xenograft MCF-7 tumors verified its potent anti-tumor efficacy with complete tumor elimination.