A hybrid nanogel as nanosponge for tumor differentiated sonodynamic therapy

A hybrid nanogel called a nanosponge was prepared for diverse sonotherapeutic treatment of hypoxic and normoxic tumor sections. A dextrin derivative with a loss spatial structure was defined as the expansive state of the nanosponge. Protoporphyrin IX and phenylboronic acid (PBA) decorated on the dextrin skeleton reduced the self-quenching of the sonosensitizer and endowed the nanosponge with ATP binding ability. Then, MnO₂ nanoparticles were introduced as a "nano-lock" to condense the dextrin loss structure and form a hybrid nanogel. This was defined as the compressive state of the nanosponge, which could reduce the sonotoxicity of normal cells, while PBA distributed on the surface still endowed the nanosponge with tumor-targeting ability. Notably, the nanosponge could be "unlocked" by glutathione in tumor cells, followed by recovery into the expansive state, and the elevated H₂O₂ within acidic tumor microenvironment could accelerate this process. The nanosponge could enhance the sonodynamic therapy efficiency by reducing the self-quenching of the sonosensitizer in the normoxic region. At the same time, it also could achieve satisfactory sonotherapy by reducing endogenous oxygen consumption in the hypoxic region. Our research provides novel insights into the complex interplay between sonotherapy and endogenous consumption in malignancies, potentially revolutionizing tumor management strategies.