Sono-activable and biocatalytic 3D-printed scaffolds for intelligently sequential therapies in osteosarcoma eradication and defect regeneration.

To mitigate the necessity for multiple invasive procedures in treating malignant osteosarcoma, an innovative therapeutic approach is imperative to achieve controllable tumor-killing effects and subsequent bone repair. Here, we propose the de novo design of sono-activable and biocatalytic nanoparticles-modified 3D-printed hydroxyapatite (HA) scaffold (HS-ICTO) for intelligently sequential therapies in osteosarcoma eradication and bone defect regeneration. The engineered HS-ICTO scaffold displays superior, spatiotemporally controllable HO-catalytic performances, which promptly generate massive reactive oxygen species via multienzyme-like mechanisms coupled with sono-activation, thus augmenting tumor cell apoptosis. Furthermore, HS-ICTO can intelligently switch to catalyze HO to O within the inflammatory bone defect microenvironment, effectively blocking endogenous HO-mediated oxidative stress, which positively modulates the osteogenic differentiation of stem cells and ultimately facilitates defect regeneration. We validate that this multifaceted HS-ICTO scaffold possesses robust and on-demand abilities to prevent neoplastic recurrence and promote anti-inflammatory osseous tissue repair, representing a promising platform for precision oncological intervention and regenerative medicine.