Liver-inspired decellularized hydrogel platform to eradicate osteosarcoma and reconstruct bone defects.

Abstract

Osteosarcoma (OS), the most prevalent primary malignant bone tumor, presents significant clinical challenges following surgical resection, including irregularly-shaped bone defects, residual microtumors, and inadequate bone regeneration. Inspired by the liver's remarkable regenerative capacity, an injectable hydrogel was fabricated from liver-decellularized extracellular matrix (dECM) by incorporating liposomes co-loaded with gold nanoparticles (GNPs) and doxorubicin (DOX), which was designated as GL/DOX@dECM. Functionally, this hydrogel exhibited prominent thermosensitivity, enabling facile injection and conformity to irregular defects. Under near-infrared laser irradiation, the GNPs-mediated photothermal effect combined with DOX chemotherapy to induce tumor cell apoptosis, effectively suppressing OS growth in subcutaneous models. More importantly, the native liver-specific ECM-enriched GL/DOX@dECM provided osteogenesis-conducive biochemical and biomechanical cues. RNA sequencing confirmed that it markedly enhanced cytoskeletal remodeling and integrin-mediated adhesion, alongside significant enrichment of key osteogenic pathways including mitogen-activated protein kinases and transforming growth factor-β, thereby promoting the in vitro osteogenic differentiation of marrow mesenchymal stem cells. Critically, the GL/DOX@dECM prompted substantial new-bone formation in the cranial defect model, evidenced by a bone volume/total volume ratio of 41.76% ± 11.41% after eight weeks post-implantation. In summary, the liver-inspired injected decellularized hydrogel platform presented a highly-promising strategy for treating refractory bone defects following OS resection.