Renal-Clearable Metalloporphyrin Complex-Based Nanosonosensitizers Using Photoacoustic Imaging Guiding to Enhance Sonodynamic Cancer Therapy

Sonodynamic therapy (SDT) is a noninvasive approach to tumor treatment, with ongoing efforts being focused on developing highly effective sonosensitizers with low toxicity. Herein, a liquid-phase stripping technique was introduced as a simple reflux method for synthesizing ultrasmall Mn-PCN-224 nanodots (MM NDs). Compared with PCN-224 nanodots, the synthesized MM NDs, which function as renal-clearable nanoagents, produced 2.42 times more reactive oxygen species (ROS) under identical ultrasound (US) irradiation conditions. In vivo and in vitro experiments revealed that A549 lung cancer cells treated with MM NDs under US irradiation and H2O2 exhibited a relative cell viability of ∼9% and a tumor inhibition rate of ∼91%. This result demonstrates that MM NDs can efficiently increase the effectiveness of SDT by leveraging their catalase-like activity and ultrasmall size (4 nm) to prevent ROS quenching. Furthermore, these nanoagents could be effectively utilized for photoacoustic (PA) imaging to track their accumulation in tumors and monitor the alleviation of the hypoxic tumor microenvironment. Notably, MM ND-mediated SDT demonstrated superior penetration depth compared to PDT, making it more effective in inhibiting contralateral tumors while facilitating deep-tissue treatment. Thus, this study introduces renal-clearable nanoagents with promising potential for PA-guided SDT, thereby paving the way for more effective tumor treatment strategies.