Photosynthetic Oxygenation-Augmented Sonodynamic Nanotherapy of Hypoxic Tumors

Reactive oxygen species (ROS) has been employed as a powerful therapeutic agent for eradicating tumor via oxidative stress. As an emerging ROS-involving noninvasive anticancer therapeutic modality, sonodynamic therapy (SDT) with high tissue penetration depth and benign remote spatiotemporal selectivity has been progressively utilized as the distinct alternative for ROS-based tumor treatment. However, the hypoxic tumor microenvironment substantially restricts the sonodynamic effect. In this work, an oxygen self-sufficient hybrid sonosensitizer on the basis of photosynthetic microorganisms cyanobacteria (Cyan) integrated with ultrasmall oxygen-deficient bimetallic oxide Mn 1.4 WO x nanosonosensitizers, termed as M@C, is designed and engineered to overcome the critical issue of hypoxia-induced tumor resistance and strengthen the SDT effect. The sustained photosynthetic oxygen production by Cyan under light illumination can promote Mn 1.4 WO x nanosonosensitizers to produce more ROS against cancer cells both in vitro and in vivo under ultrasound (US) irradiation. Especially, the sustained oxygen evolution for suppressing the gene expression of hypoxia-inducible factor 1alpha (HIF-1 α ) further boosts and augments the SDT efficiency. Thus, this work provides the paradigm that the rationally engineered biohybrid microorganism-based multifunctional sonosensitizers can serve as an effective bioplatform for augmenting the therapeutic efficiency of SDT, particularly for the treatment of hypoxic tumors.