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 Mn1.4 WOx 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 Mn1.4 WOx 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-1α) 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.