A new study has combined living bacterial sonosensitizers with ultrasound-mediated tissue remodeling to improve bacterial accumulation and penetration in tumors, offering a potential strategy to enhance sonodynamic cancer therapy.

The study was led by Prof. CAI Lintao from the Shenzhen Institutes of Advanced Technology (SIAT) of the Chinese Academy of Sciences (CAS) and published in Advanced Functional Materials.

Sonodynamic therapy has emerged as a promising non-invasive approach for treating deep-seated tumors due to the deep tissue penetration of ultrasound. However, poor tumor accumulation and limited penetration of sonosensitizers remain major challenges that compromise its therapeutic efficacy.

In this study, the researchers used Rhodopseudomonas palustris (R.P) as a living sonosensitizer, taking advantage of its natural hypoxia-directed motility for tumor targeting and penetration. Transwell and 3D tumor spheroid assays confirmed its directional migration and progressive penetration into tumor interiors. Ultrasound further enhances bacterial delivery by remodeling tumor vasculature and increasing tissue permeability.

Bacteriochlorophyll (BChl), naturally present in R.P, acts as an intrinsic sonosensitizer generating reactive oxygen species (ROS), including singlet oxygen and hydroxyl radicals, under ultrasound stimulation. TD-DFT calculations revealed a low excitation energy of 2.1609 eV and a HOMO-LUMO gap of 2.54 eV, providing insight into its sonosensitizing activity.

Beyond activating BChl, ultrasound induces rapid and reversible dilation of tumor blood vessels. Reduced ZO-1 staining and increased dextran extravasation indicated transient disruption of endothelial junctions and enhanced vascular permeability. Molecular dynamics simulations further showed that cyclic mechanical forces alter lipid membrane structure and organization, providing a possible explanation for ultrasound-facilitated transport across vascular barriers.

Photoacoustic imaging and histological analysis confirmed that ultrasound significantly improved bacterial accumulation and deep penetration within tumors. Together, bacterial sonosensitization and ultrasound-mediated tissue remodeling enhanced antitumor efficacy in vitro and in vivo, with a favorable biosafety profile.

According to the researchers, this approach combines the natural hypoxia-targeting ability of R.P with the dual effects of ultrasound, which enhances vascular permeability to facilitate bacterial accumulation and deep tumor penetration while activating ROS production for tumor cell destruction.

Without requiring complex chemical synthesis or genetic modification, this living bacterial sonosensitizer addresses key limitations of conventional sonodynamic therapy and offers a promising strategy for cancer therapy, the researchers said.