Controlled domain gels with a wide stiffness gradient simultaneously promote bone regeneration and suppress tumor recurrence through DAPK activity

The reconstruction of bone defects following bone tumor resection pose significant challenges, including high risks for tumor recurrence. To address these challenges, we designed controlled-domain gels that possessed exceptional anti-tumorigenic effectiveness and osteogenic activity. This was achieved through the selection of an amino-acid-based low-molecular-weight gels (LMWGs) with superior biocompatibility and antitumor efficacy, and further construction of three-domain structure with a large-range stiffness gradient, through the assembly/disassembly of LMWGs inside a stable methacrylated alginate (AlgMA) network using photopolymerization. Such layered design not only constructed a top anti-tumorigenic domain at 0.6 kPa and a bottom osteogenic domain at 500 kPa, allowing for selectively inducing tumor cell apoptosis and promoting osteogenic differentiation of mesenchymal stem cells (MSCs), but also generated a gradient selectively confining the migration of tumor cells along soft-to-hard direction, without affecting the recruiting of MSCs toward the injury sites. In particular, the critical involvement of the DAPK-mediated signaling cascades might lead to the selected apoptosis of tumor cells on LMWG domain. The in-vivo results further suggested that multi-domain gel effectively inhibited tumor growth and displayed excellent bone-forming activity. Overall, such strategies could advance our fundamental understanding of the bone tumor postoperative treatment, in addition to offering new therapeutic opportunities.