Ultrasound‐Responsive 4D Bioscaffold for Synergistic Sonopiezoelectric‐Gaseous Osteosarcoma Therapy and Enhanced Bone Regeneration

Various antitumor strategies have emerged to address the escalating need for effective tumor eradication. However, achieving precise and spatiotemporally controlled dynamic therapies remains promising yet challenging. Sonopiezoelectric nanotherapy eliminates tumor cells by generating reactive oxygen species (ROS) through ultrasound stimulation, enabling spatiotemporal control and ensuring safety during deep tissue penetration. In this study, a hybrid bioscaffold incorporating few-layer black phosphorus (BP) and nitric oxide (NO) donors are rationally designed and engineered for sonopiezoelectric-gaseous synergistic therapy. This ultrasound-responsive system provides a stepwise countermeasure against tumor invasion in bone tissues. Ultrasonic vibration induces mechanical strain in BP nanosheets, leading to piezoelectric polarization and subsequent ROS generation. Moreover, ultrasound-triggered NO burst release from the donors enables spatiotemporally controlled gas therapy. The synergistic effects of sonopiezoelectric therapy and ultrasound-excited gas therapy enhance tumor eradication, effectively inhibiting tumor proliferation and metastasis while minimizing off-target cytotoxicity. Additionally, the biomineralization capability of degradable BP and proangiogenic effects of low-concentration NO establish the hybrid bioscaffold as a bioactive platform that facilitates subsequent bone regeneration. The development of this 4D multifunctional therapeutic platform, characterized by superior sonopiezoelectric efficacy, controlled NO release, and stimulatory effects on tissue regeneration, offers new insights into the comprehensive treatment of invasive bone tumors.