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

Abstract

ABSTRACT Essential micronutrient Vitamin B 2 (VB 2 ) is a bioactive compound with sonodynamic activity; however, it suffers from hydrophilic limitations. Herein, a dynamic prodrug nanocomplex (PTX‐PBA/VB 2 ) was constructed via phenylboronic acid‐diol interaction between VB 2 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 ( 1 O 2 ) 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/VB 2 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.