Endogenous Exothermic Reaction‐Driven Pyroelectric Osteosarcoma Therapy

ABSTRACT Pyroelectric tumor therapy, an emerging antitumor modality relying on biocompatible pyroelectric materials to induce intertumoral catalytic reactions, has long been constrained by the requirement for conventional exogenous excitation. To address this limitation, we engineered an endogenous exothermic reaction‐driven pyroelectric three‐dimensional (3D) composite scaffold by screening three representative nanoparticles (CaO, CaO 2 , and MgO 2 ), which can generate significant heat at tumor sites upon exothermic reaction. We selected the highest‐performing exothermic reaction CaO nanoparticles and incorporated them into a CaO/Bi 13 S 18 I 2 ‐loaded polycaprolactone scaffold (denoted as BC‐PCL) for subsequent synergistic osteosarcoma treatment and bone regeneration. Upon tumor‐site implantation, the CaO component undergoes rapid hydrolysis, releasing calcium ions (Ca 2+ ) and generating localized heat. This endogenous exothermic energy activates the pyroelectric Bi 13 S 18 I 2 phase to produce high levels of cytotoxic reactive oxygen species (ROS), enabling tumor regression while facilitating Ca 2+ ‐mediated scaffold‐guided bone regeneration under physiological conditions. This dual‐function system establishes a unique self‐triggered, stepwise therapeutic cascade for efficient osteosarcoma therapy. In vitro and in vivo studies demonstrate that BC‐PCL‐derived ROS induces mitochondrial membrane potential depolarization and nuclear DNA damage, culminating in cancer cell apoptosis. Concurrently, the 3D‐printed scaffold promotes osteogenic differentiation via Ca 2+ ‐mediated enhancement of cellular proliferation and osteoblastogenesis. This work introduces a paradigm‐shifting strategy for osteosarcoma therapy, leveraging endogenous exothermic reactions to bypass the need for external excitation while integrating tumor eradication with bone tissue regeneration.