Cascade-activatable NO release based on GSH-detonated nanobomb for multi-pathways cancer therapy

Therapeutic approaches of combining conventional photodynamic therapy (PDT) with other adjuvant treatments to sensitize PDT represent an appealing strategy. Herein, a novel synergetic nanobomb strategy based on glutathione (GSH)-responsive biodegradation was proposed to effectively destroy tumors expeditiously and accurately. This nanobomb was rationally constructed via the simultaneous encapsulation of methylene blue (MB) and L-arginine (L-Arg) into polyethylene glycol (PEG) modified mesoporous organosilicon nanoparticles (MON). The resulting L-Arg/MB@MP initially exhibited prolonged blood circulation, improved bioavailability, and enhanced tumor accumulation in mice after tail vein injection according to the pharmacokinetic investigations, before the nanoparticles were entirely excreted. Under laser irradiation, L-Arg/MB@MP produced remarkable reactive oxygen species (ROS) directly for PDT therapy, while a portion of ROS may oxidize L-Arg to generate nitric oxide (NO) not only for gas therapy (GT) but also serve as a biological messenger to regulate vasodilation to alleviate the tumor hypoxia. Subsequently, the rapidly released NO was further oxidized to reactive nitrogen species, which together with ROS promote immunogenic cell death by inducing G2/M cell-cycle arrest and apoptosis in cancer cells, and eventually resulting in enhanced anti-tumor immune responses. Moreover, the GSH depletion in tumor tissues induced by L-Arg/MB@MP biodegradation can cooperate with GT to amplify the therapeutic effect of PDT. These results demonstrate that this nanobomb provides new ideas for clinical translation to treat tumor patients in terms of synergistic PDT-GT nanotherapy in hypoxic-solid tumors.

Automated summary

The study proposes a novel synergetic nanobomb strategy based on GSH-responsive biodegradation for efficient destruction of tumors. This strategy combines photodynamic therapy with gas therapy and uses reactive oxygen species and nitric oxide to regulate tumor hypoxia and induce tumor cell death, leading to enhanced anti-tumor immune responses.