Dynamic Covalent Prodrug Nanocomplex for Ultrasound-Triggered Oxidative Stress Amplification and Synergistic Sonochemotherapy.

Essential micronutrient Vitamin B2 (VB2) is a bioactive compound with sonodynamic activity; however, it suffers from hydrophilic limitations. Herein, a dynamic prodrug nanocomplex (PTX-PBA/VB2) was constructed via phenylboronic acid-diol interaction between VB2 and phenylboronic acid-functionalized paclitaxel prodrug (PTX-PBA). This reversible boronate ester linkage ensures colloidal stability while enabling external stimuli- or tumor microenvironment-triggered drug release. Under ultrasound irradiation, the nanocomplex generates singlet oxygen (1O2) and hydroxyl radical, inducing prodrug cleavage, on-demand paclitaxel release, glutathione depletion, and glutathione peroxidase 4 downregulation, leading to amplified oxidative stress and immunogenic cell death. Prolonged intratumoral retention (>7 days) was realized by loading PTX-PBA/VB2 nanocomplex into an injectable poly(amino acid) hydrogel. In vivo study presented remarkable tumor suppression in 4T1-bearing mice, attributed to enhanced intratumoral reactive oxygen species levels and lipid peroxidation accompanied by robust immune activation. This work establishes a promising dynamic covalent prodrug strategy for precise sonoimmunotherapy.