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

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 BiOIO3 nanosheets to obtain the injectable sono-piezoelectric/pyroelectric peptide hydrogels (KLD-PFS@BiOIO3) featuring a supramolecular peptide nanofiber (SMPNF) structure. Differing from the dominant BaTiO3 in sono-piezoelectric dynamic therapy (SPDT) of cancer, BiOIO3 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.