Liquid Metal Multi-Functional Droplets Enabled High-Performance Tumor Therapy With Four Synergistic...

Cryoablation, which induces rapid intracellular ice crystal formation, has been widely used in clinics for treating various tumors, yet monotherapy yields limited efficacy due to inadequate elimination of tumor cells. Here, we proposed an effective synergistic strategy with intelligent biomaterials to overcome the limitation of conventional cryo-thermal therapy that requires two separate devices, integrating cryo-thermal ablation, mechanical destruction, and drug release to improve therapeutic efficacy. A sodium alginate (SA) modified iron-containing liquid metal microdroplet (FLMM@DOX@SA) was fabricated with diverse intelligent merits under stimulation. Under cooling, FLMM@SA would go through a multi-phase transition process and present a unique "bomb-explosion-like" behavior, leading to fierce mechanical destruction (more than 6.3 MPa) to surrounding ice crystals. Then, FLMM@SA was demonstrated as a powerful magnetocaloric agent when subject to an alternating magnetic field. In addition, this intelligent biomaterial exhibited stimulus-enhanced drug release across multiple cues, including cryo-stimulation, magnetothermal activation, and pH changes, thereby driving synergistic antitumor efficacy with the highest fraction of necrotic cells. The mechano-thermal-chemo-freezing synergistic therapy further verified the effective destructive performance with robust tumor growth suppression and a 100% animal survival rate. Collectively, this work highlights the integration of intelligent biomaterials into cryoablation, thereby forging a novel modality for highly effective combination therapy.