Porphyrin-based nanoscale metal-organic framework nanocarriers entrapping platinum nanoparticles and S-nitrosoglutathione for sonodynamic therapy in hypoxic tumors.

Sonodynamic therapy (SDT), which employs acoustic energy to generate reactive oxygen species (ROS), has emerged as a promising strategy for tumor treatment. While ultrasound (US) offers deep tissue penetration and minimal invasiveness, the low energy conversion efficiency of sonosensitizers and the hypoxic tumor microenvironment (TME) significantly limit SDT efficacy. To overcome these challenges, we developed a nano-sonosensitizer, TBP-Hf@Pt-GSNO (Hf-Pt-G), composed of a porphyrin-based nanoscale metal-organic framework (nMOF), TBP-Hf, integrated with platinum nanoparticles (Pt NPs) and S-nitrosoglutathione (GSNO). Pt NPs within the nMOF cavities enhance ultrasound reflection and scattering, thereby improving the acoustic energy conversion efficiency of TBP and boosting SDT efficacy. In addition, Pt NPs can catalyze the conversion of endogenous hydrogen peroxide (H2O2) into oxygen to alleviate tumor hypoxia. US irradiation further triggers the release of nitric oxide (NO) from GSNO, amplifying the killing effect on tumor cells. Enhanced singlet oxygen (1O2) generation and decreased hypoxia inducible factor-1α (HIF-1α) expression were observed in tumor cells following Hf-Pt-G treatment with US irradiation. In vivo, significant tumor suppression was achieved in 4T1 tumor-bearing mice treated with Hf-Pt-G combined with US. This study presents a novel strategy for enhancing acoustic energy conversion while integrating hypoxia alleviation and controllable NO release, thus improving the therapeutic outcomes of SDT.