Mesenchymal Stem Cell-Based CO₂-Bubble-Generating Liposomes for Targeted and Controlled Chemotherapy

Chemotherapeutic agents are widely used in cancer treatment but often induce severe off-target toxicity due to their nonspecific distribution. To address this limitation, we developed an innovative mesenchymal stem cell-based drug delivery system incorporating doxorubicin encapsulated in CO₂-bubble-generating thermosensitive liposomes (MSC-DOX-BG-LPs) for controlled and tumor-targeted DOX release under near-infrared (NIR) irradiation. MSCs inherently migrate to tumor tissues via CXCR4-CXCL12 chemotactic signaling, enabling precise tumor targeting. MSC-DOX-BG-LPs remain stable during systemic circulation and regulate DOX release in response to heat-induced liposomal destabilization and CO₂ bubble formation, ensuring localized drug activation while minimizing systemic side effects. In vitro and in vivo experiments demonstrated that MSC-DOX-BG-LPs, upon NIR irradiation, effectively inhibited tumor proliferation and angiogenesis while inducing apoptosis in tumor cells (***P < 0.001). Importantly, MSC-mediated delivery significantly enhanced drug accumulation within the tumor microenvironment, overcoming limitations associated with passive liposomal carrier delivery. These findings highlight MSC-DOX-BG-LPs as a promising platform for targeted chemotherapy that integrates tumor-specific migration with externally controlled drug release. This approach has the potential to improve therapeutic outcomes and prolong the survival of patients with various solid tumors.