Stromal Cells Recruitment by Sono‐Piezoelectric/Pyroelectric Peptide Hydrogels Promotes Bone Regeneration After Postsurgical Osteosarcoma Recession: A Real‐World‐Matched Study

ABSTRACT Currently, the elimination of postsurgical osteosarcoma (OS) and defect repair are still separately explored, which is unlike real‐world clinical scenarios. Inadequate bone marrow stromal cells (BMSCs) compromise their repair and antitumor efficiencies. Here, PFSSTKT (PFS)‐functionalized KLD‐12 peptide hydrogels (KLD‐PFS) have been engineered and integrated with 2D BiOIO 3 nanosheets to obtain the injectable sono‐piezoelectric/pyroelectric peptide hydrogels (KLD‐PFS@BiOIO 3 ) featuring a supramolecular peptide nanofiber (SMPNF) structure. Differing from the dominant BaTiO 3 in sono‐piezoelectric dynamic therapy (SPDT) of cancer, BiOIO 3 nanosheets can produce ROS through sono‐piezoelectric and pyroelectric catalytic processes under ultrasound irradiation, thus enabling the combination of SPDT with pyroelectric dynamic therapy against residual OS. More significantly, PFS as a bone marrow homing peptide enables KLD‐PFS to capture and recruit more BMSCs, and the inherent SMPNF structure, direct ultrasound‐induced current stimuli, sono‐piezoelectricity/pyroelectricity‐induced current stimuli and ROS birth expedite BMSCs differentiation and bone regeneration. These multifaceted actions follow the signaling pathways associated with calcium flux and cancer–neuron communication disruptions and metabolic dysfunction rectification. They have been successfully validated to repress residual OS and favor bone regeneration in a clinical scenarios‐matched postsurgical osteosarcoma and bone defect model. This study offers a promising strategy for comprehensive osteosarcoma management.