Herein, an acid-responsive liposomal nanodrug was developed for photoacoustic (PA) imaging-guided oxygen (O2)-independent sonodynamic therapy (SDT). This liposomal nanodrug offers several advantages: (i) it facilitates O2-independent alkyl radical generation upon ultrasound irradiation, (ii) it exhibits acid-responsive charge reversion that enhances tumor penetration, and (iii) it enables activated PA imaging for therapeutic feedback.