An "Outer Piezoelectric and Inner Epigenetic" Logic-Gated PANoptosis for Osteosarcoma Sono-Immunotherapy and Bone Regeneration.

The precise manipulation of PANoptosis, a newly defined cell death pathway encompassing pyroptosis, apoptosis, and necroptosis, is highly desired to achieve safer cancer immunotherapy with tumor-specific inflammatory responses and minimal side effects. Nonetheless, this objective remains a formidable challenge. Herein, an "AND" logic-gated strategy for accurately localized PANoptosis activation, utilizing composite 3D-printed bioactive glasses scaffolds integrated with epigenetic regulator-loaded porous piezoelectric SrTiO nanoparticles is proposed. The "logic-gated" strategy is co-programmed by an "outer" input signal of exogenous ultrasound irradiation to produce reactive oxygen species and an "inner" input signal of acid tumor microenvironment to ensure the epigenetic demethylation regulation, guaranteeing the tumor-specific PANoptosis. Specifically, immunogenic PANoptosis triggers dendritic cell maturation and cytotoxic T cell activation, amplifying antitumor immune responses and significantly suppressing osteosarcoma growth, with a suppression rate of ≈73.47 ± 5.2%. In addition, the well-known bioactivities of Sr-doped scaffolds expedite osteogenic differentiation and reinforce bone regeneration. Therefore, this work provides a paradigm of logic-gated sono-piezoelectric biomaterial platform with concurrently exogenous/endogenous activated PANoptosis for controlled sono-immunotherapy of osteosarcoma, and related bone defects repair.