Dual-functional MXene-integrated GelMA microspheres for synergistic chemo/photothermal therapy: In vitro 2D/3D multi-cancer evaluation and in vivo breast cancer validation.

This study reports a microfluidic strategy for the fabrication of monodisperse gelatin methacryloyl (GelMA) microspheres co-encapsulating photothermal agents and chemotherapeutic drugs for synergistic cancer therapy. Soybean phospholipid modification was applied to improve the colloidal stability and biocompatibility of MXene nanosheets (MXene-SP), which simultaneously served as photothermal transducers and drug carriers. Temozolomide (TMZ) or doxorubicin (DOX) were first loaded onto MXene-SP and subsequently encapsulated into GelMA microspheres through a flow-focusing microfluidic platform, resulting in highly uniform and size-controlled drug delivery systems. The therapeutic performance of the developed microspheres was first evaluated using U87-MG glioblastoma and MCF-7 breast cancer models. Under near-infrared (NIR) irradiation, MXene-SP-loaded microspheres exhibited efficient photothermal responsiveness, reaching temperatures above 50 °C and enabling NIR-triggered drug release. Combined chemo-photothermal treatment significantly enhanced anticancer efficacy compared with monotherapy in both two-dimensional (2D) monolayer cultures and three-dimensional (3D) tumor spheroid models. In addition, the microsphere system demonstrated improved local retention and sustained therapeutic effects compared with free MXene treatment. To further validate the therapeutic potential in vivo, an orthotopic breast cancer mouse model was established for localized microsphere treatment. The combined MXene-SP and DOX treatment under NIR irradiation exhibited the most significant tumor suppression among all treatment groups without obvious systemic toxicity. Collectively, this study presents a tunable MXene-integrated GelMA microsphere platform with controllable fabrication, localized retention capability, and NIR-responsive therapeutic functionality, highlighting its potential for localized combinational cancer therapy.